Heterobifunctional compounds and methods of treating disease

Abstract

The present invention provides heterobifunctional compounds capable of binding to both the androgen receptor and BRD4 (bromodomain-containing protein 4). Also provided are pharmaceutical compositions comprising the heterobifunctional compounds and their use in the treatment of diseases such as cancer.

Description

[0001] Cross - Reference to Related Applications

[0002] This application claims the benefit and priority of U.S. Provisional Patent Application No. 63 / 494,406, filed on April 5, 2023, and U.S. Provisional Patent Application No. 63 / 404,569, filed on September 8, 2022; the content of each patent application is hereby incorporated by reference. Field of the Invention

[0003] The present invention provides hetero - bifunctional compounds, pharmaceutical compositions, and their use in treating diseases such as cancer. Background Art

[0004] Despite a large amount of research work and scientific progress reported in the literature regarding the treatment of cancer, this disease remains a major health problem. Solid tumors, including prostate cancer, breast cancer, and lung cancer, remain highly prevalent in the world population. The incidence of prostate cancer increases with age, and as the lifespan of human subjects increases, the number of patients suffering from prostate cancer continues to increase correspondingly. Breast cancer is one of the most common cancers in women and is a major cause of death in women aged 50 - 55. Lung cancer is the leading cause of death among cancer patients, with more than 85% of lung cancers being non - small cell lung cancer (NSCLC). Many lung cancers are attributed to smoking. Current treatment options for these cancers are not effective for all patients and / or may have substantial adverse side effects.

[0005] There is a need for new therapies to address this unmet need in cancer treatment. In particular, there is a need for new therapies that achieve anti - cancer effects via mechanisms different from those of common therapies. Exemplary mechanisms of common anti - cancer therapies include (a) DNA alkylation that limits the ability of cells to reproduce, (b) topoisomerase inhibition, where the therapeutic agent inhibits the activity of topoisomerase, thereby restricting the separation of DNA strands, and (c) mitosis inhibition, where the therapeutic agent reduces the ability of cells to divide. New therapies that achieve anti - cancer effects via different mechanisms provide an opportunity to treat cancer more effectively and / or treat cancers that are resistant to currently available drugs.

[0006] The present invention addresses the foregoing needs and provides other related advantages. Summary of the Invention

[0007] The present invention provides hetero - bifunctional compounds, pharmaceutical compositions, and their use in treating diseases such as cancer. In particular, one aspect of the present invention provides a series of hetero - bifunctional compounds, such as the compounds represented by Formula I:

[0008]

[0009] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in the detailed description. Further description of a series of additional heterobifunctional compounds is described in the detailed description. The compounds can be part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier.

[0010] Another aspect of the invention provides a series of heterobifunctional compounds, such as the compounds represented by Formula II:

[0011]

[0012] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in the detailed description. Further description of a series of additional heterobifunctional compounds is described in the detailed description. The compounds can be part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier.

[0013] Another aspect of the invention provides a method for treating cancer. The method comprises administering to a patient in need a therapeutically effective amount of a compound described herein, such as a compound of Formula I or Formula II, to treat cancer.

[0014] Another aspect of the invention provides a method for causing cancer cell death. The method comprises contacting cancer cells with an effective amount of a compound described herein, such as a compound of Formula I or Formula II, to cause cancer cell death. Detailed Description

[0015] The present invention provides heterobifunctional compounds, pharmaceutical compositions and their use in treating diseases such as cancer. Unless otherwise indicated, the practice of the present invention employs conventional techniques of organic chemistry, pharmacology, molecular biology (including recombinant techniques), cell biology, biochemistry and immunology. Such techniques are explained in the literature, such as "Comprehensive Organic Synthesis" (eds. B.M. Trost and I. Fleming, 1991 - 1992); "Handbook of experimental immunology" (eds. D.M. Weir and C.C. Blackwell); "Current protocols in molecular biology" (eds. F.M. Ausubel et al., 1987, and updated periodically); and "Current protocols in immunology" (eds. J.E. Coligan et al., 1991), each incorporated herein by reference in its entirety.

[0016] Aspects of the invention are set forth in the sections below; however, aspects of the invention described in a particular section are not limited to any particular section. Further, when a variable is not accompanied by a definition, the previous definition of the variable applies.

[0017] Definitions

[0018] The compounds of the invention include those generally described herein and are further illustrated by the classes, subclasses, and species disclosed herein. Unless otherwise indicated, the following definitions apply as used herein. These definitions apply whether the term is used by itself or in combination with other terms. Thus, the definition of "alkyl" applies to the "alkyl" portion of "alkyl" as well as "-O-alkyl" and the like. For purposes of the present invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Edition. Additionally, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999 and "March's Advanced Organic Chemistry", 5th Edition, Smith, M.B. and March, J. eds., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0019] As used herein, the term "aliphatic" or "aliphatic group" means a straight-chain (i.e., unbranched) or branched-chain, substituted or unsubstituted hydrocarbon chain that is completely saturated or contains one or more unsaturated units, or a monocyclic or bicyclic hydrocarbon that is completely saturated or contains one or more unsaturated units but is not aromatic (also referred to herein as "alicyclic") and has a single point of attachment to the remainder of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, "alicyclic" refers to a monocyclic C3-C6 hydrocarbon that is completely saturated or contains one or more unsaturated units but is not aromatic and has a single point of attachment to the remainder of the molecule. Suitable aliphatic groups include, but are not limited to, straight-chain or branched-chain, substituted or unsubstituted alkyl, alkenyl, alkynyl, and their hybrids, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0020] As used herein, the term "bicyclic" or "bicyclic system" refers to any bicyclic system, i.e., a carbocyclic or heterocyclic ring, saturated or having one or more unsaturated units, with one or more shared atoms between the two rings of the ring system. Thus, the term includes any permissible ring fusion, such as ortho-fusion or spiro-fusion. As used herein, the term "heterobicyclic" is a subgroup of "bicyclic" that requires one or more heteroatoms to be present in one or both rings of the bicyclic. Such heteroatoms can be present at the ring junctions and are optionally substituted, and can be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, etc. In some embodiments, the bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. As used herein, the term "bridged bicyclic" refers to any bicyclic system, i.e., a carbocyclic or heterocyclic ring, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a "bridge" is an unbranched chain of atoms or an atom or valence bond connecting two bridgeheads, where a "bridgehead" is any skeletal atom of the ring system that is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, the bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those groups set forth below, where each group is attached to the remainder of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, the bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of the bridged bicyclic group is optionally substituted. Exemplary bicyclics include:

[0021]

[0022] Exemplary bridged bicyclics include:

[0023]

[0024] The term "lower alkyl" refers to a C 1-4 straight or branched chain alkyl. Exemplary lower alkyls are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0025] The term "lower haloalkyl" refers to a C 1-4 straight or branched chain alkyl substituted with one or more halogen atoms.

[0026] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; any quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocycle, e.g., N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR+ (such as in an N - substituted pyrrolidinyl).

[0027] As used herein, the term "unsaturated" means that the moiety has one or more unsaturated units.

[0028] As used herein, the term "divalent C 1-8 (or C 1-6 ) saturated or unsaturated, straight - chain or branched - chain hydrocarbon chain" refers to straight - chain or branched - chain divalent alkylene, alkenylene, and alkynylene chains as defined herein.

[0029] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is polymethylene, i.e., -(CH2) n -, where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. A substituted alkylene chain is a polymethylene in which one or more methylene hydrogen atoms are replaced by substituents. Suitable substituents include those described below for substituted aliphatic groups.

[0030] The term "-(C0 alkylene)-" refers to a bond. Thus, the term "-(C 0-3 alkylene)-" encompasses a bond (i.e., C0) and a -(C 1-3 alkylene)- group.

[0031] The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene containing at least one double bond and in which one or more hydrogen atoms are replaced by substituents. Suitable substituents include those described below for substituted aliphatic groups.

[0032] The term "halogen" means F, Cl, Br, or I.

[0033] The term "aryl", used alone or as part of a larger moiety such as in "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to a monocyclic or bicyclic system having a total of five to fourteen ring members, where at least one ring in the system is aromatic and each ring in the system contains 3 to 7 ring members. The term "aryl" can be used interchangeably with the term "aryl ring". In certain embodiments of the present invention, "aryl" refers to an aromatic ring system, including but not limited to phenyl, biphenyl, naphthyl, anthracenyl, etc., which may bear one or more substituents. As used herein, groups in which an aromatic ring is fused to one or more non - aromatic rings, such as indanyl, phthalimido, naphthalimido, phenanthridinyl, or tetrahydronaphthyl, etc., are also included within the scope of the term "aryl". The term "haloaryl" refers to an aryl substituted with at least one halogen. Exemplary haloaryls include chlorophenyl (e.g., 3 - chlorophenyl, 4 - chlorophenyl), fluorophenyl, etc. The term "phenylene" refers to a divalent phenyl group.

[0034] The terms "heteroaryl" and "heteroar-" when used alone or as part of a larger moiety (e.g., "heteroarylalkyl" or "heteroaryloxy") refer to a group having 5 to 10 ring atoms, preferably 5, 6 or 9 ring atoms; having 6, 10 or 14 π electrons shared in a ring array; and having one to five heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen or sulfur and includes any oxidized form of nitrogen or sulfur and any quaternized form of basic nitrogen. Heteroaryl includes, but is not limited to, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl and pteridinyl. As used herein, the terms "heteroaryl" and "heteroar-" also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic or heterocyclic rings, and unless otherwise specified, the linking group or point of attachment is on the heteroaromatic ring or on one of the rings fused to the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuryl, dibenzofuryl, indazolyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl and tetrahydroisoquinolinyl. Heteroaryl can be monocyclic or bicyclic. The term "heteroaryl" can be used interchangeably with the terms "heteroaryl ring", "heteroaryl" or "heteroaromatic", any of which includes an optionally substituted ring. The term "heteroarylalkyl" refers to an alkyl group substituted with a heteroaryl group, wherein the alkyl and heteroaryl moieties are independently optionally substituted. The term "haloheteroaryl" refers to a heteroaryl group substituted with at least one halogen. Exemplary haloheteroaryls include chloropyridine, fluoropyridine, chloropyrazole, fluoropyrazole, etc. The term "heteroarylene" refers to a divalent heteroaryl group. Similarly, the terms "pyrazolylene", "imidazolylene" and "pyrrolylene" refer to divalent pyrazolyl, imidazolyl and pyrrolyl groups, respectively. Similarly, the terms "pyridazinylene", "pyrimidinylene", "pyrazinylene" and "pyridinylene" refer to divalent pyridazinyl, pyrimidinyl, pyrazinyl and pyridyl groups, respectively.

[0035] As used herein, the terms "heterocycle", "heterocyclic group", "heterocyclic moiety" and "heterocyclic ring" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is saturated or partially unsaturated and has one or more, preferably one to four, heteroatoms as defined above in addition to carbon atoms. When used to refer to the ring atoms of a heterocycle, the term "nitrogen" includes substituted nitrogen. For example, in a saturated or partially unsaturated ring having 0 - 3 heteroatoms selected from oxygen, sulfur or nitrogen, nitrogen can be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or +NR (such as in N-substituted pyrrolidinyl).

[0036] The heterocycle can be attached to its side group at any heteroatom or carbon atom that results in a stable structure and any one of the ring atoms can optionally be substituted. Examples of such saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxolanyl, dioxolyl, diazepanyl, oxazepanyl, thiazepanyl, morpholinyl, 2-oxa-6-azaspiro[3.3]heptane, and quinuclidinyl. The terms "heterocycle", "heterocyclic group", "heterocyclic ring", "heterocyclic moiety", "heterocyclic portion", and "heterocyclic group" are used interchangeably herein and also include groups in which the heterocyclic ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. The heterocyclic group can be monocyclic or bicyclic. The term "heterocyclic alkyl" refers to an alkyl substituted with a heterocyclic group, wherein the alkyl and heterocyclic moieties are independently optionally substituted. The term "heterocyclylene" refers to a divalent heterocyclic group. The terms "piperidinylene", "piperazinylene", and "azetidinylene" refer to divalent piperidinyl, piperazinyl, and azetidinyl, respectively.

[0037] As used herein, the term "heterocycloalkyl" refers to a saturated heterocyclic group. The term "heterocycloalkylene" refers to a divalent heterocycloalkyl.

[0038] As used herein, the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

[0039] As described herein, the compounds of the present invention can contain "optionally substituted" moieties. In general, the term "substituted", whether preceded by the term "optionally" or not, means that one or more hydrogens of the designated moiety are replaced by a suitable substituent. Unless otherwise indicated, an "optionally substituted" group can have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from the designated group, the substituents at each position can be the same or different. Combinations of substituents contemplated by the present invention are preferably those that form stable or chemically viable compounds. As used herein, the term "stable" refers to a compound that does not substantially change when subjected to conditions that allow its generation, detection, and in some embodiments, its recovery, purification, and use for one or more purposes disclosed herein.

[0040] Each optional substituent on the carbon that can be replaced is independently a monovalent substituent selected from the following: halogen; -(CH2) 0- 4R o ; -(CH2) 0-4 OR o ; -O(CH2) 0-4 R o ; -O-(CH2) 0-4 C(O)OR o ; -(CH2) 0-4 CH(OR o )2; -(CH2) 0-4 SR o ; -(CH2) 0-4 Ph, which may be substituted by R o ; -(CH2) 0-4 O(CH2) 0-1 Ph, which may be substituted by R o ; -CH=CHPh, which may be substituted by R o ; -(CH2) 0-4 O(CH2) 0-1 -pyridyl, which may be substituted by R o ; -NO2; -CN; -N3; -(CH2) 0-4 N(R o )2; -(CH2) 0- 4N(R o )C(O)R o ; -N(R o )C(S)R o ; -(CH2) 0-4 N(R o )C(O)NR o 2; -N(R o )C(S)NR o 2; -(CH2) 0-4 N(R o )C(O)OR o ; -N(R o )N(R o )C(O)R o ; -N(R o )N(R o )C(O)NR o 2; -N(R o )N(R o )C(O)OR o ; -(CH2) 0-4 C(O)R o ; -C(S)R o ; -(CH2) 0-4 C(O)ORo ; -(CH2) 0-4 C(O)SR o ; -(CH2) 0-4 C(O)OSiR o 3; -(CH2) 0-4 OC(O)R o ; -OC(O)(CH2) 0-4 SR-; SC(S)SR o ; -(CH2) 0-4 SC(O)R o ; -(CH2) 0-4 C(O)NR o 2; -C(S)NR o 2; -C(S)SR o ; -SC(S)SR o ; -(CH2) 0-4 OC(O)NR o 2; -C(O)N(OR o )R o ; -C(O)C(O)R o ; -C(O)CH2C(O)R o ; -C(NOR o )R o ; -(CH2) 0-4 SSR o ; -(CH2) 0-4 S(O)2R o ; -(CH2) 0-4 S(O)2OR o ; -(CH2) 0-4 OS(O)2R o ; -S(O)2NR o 2; -S(O)(NR o )R o ; -S(O)2N=C(NR o 2)2; -(CH2) 0-4 S(O)R o ; -N(R o )S(O)2NR o 2; -N(R o )S(O)2R o ; -N(OR o )R o ; -C(NH)NR o 2; -P(O)2R o ; -P(O)R o 2; -OP(O)R o 2; -OP(O)(OR o )2; SiRo 3; -(C 1-4 linear or branched alkylene)O-N(R o )2; or -(C 1-4 linear or branched alkylene)C(O)O-N(R o )2.

[0041] Each R o is independently hydrogen, C 1-6 aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, -CH2-(5-6 membered heteroaryl ring) or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or notwithstanding the above definition, two independently occurring R o together with one or more of their intervening atoms form a 3-12 membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be substituted on the saturated carbon atoms of R o by a divalent substituent selected from =O and =S; or each R o is optionally substituted by a monovalent substituent independently selected from: halogen, -(CH2) 0-2 R ● , -(haloalkyl R ● ), -(CH2) 0-2 OH, -(CH2) 0-2 OR ● , -(CH2) 0-2 CH(OR ● )2, -O(haloalkyl R ● ), -CN, -N3, -(CH2) 0-2 C(O)R ● , -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR ● , -(CH2) 0-2 SR ● , -(CH2) 0- 2SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR ● , -(CH2) 0-2 NR ● 2, -NO2, -SiR ● 3, -OSiR ● 3, -C(O)SR ● , -(C 1-4 linear or branched alkylene)C(O)OR ● or -SSR ● .

[0042] Each R ● is independently selected from C 1-4 aliphatic, -CH2Ph, -O(CH2) 0-1 Ph or a 5- or 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, and wherein each R ● is unsubstituted or, in the presence of a halogen group in front, is substituted only by one or more halogens; or wherein the optional substituent on the saturated carbon is independently selected from =O, =S, =NNR * 2, =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O)2R * , =NR * , =NOR * , -O(C(R * 2)) 2-3 O- or -S(C(R * 2)) 2-3 S- divalent substituents, or divalent substituents bonded to the ortho-substitutable carbon of an "optionally substituted" group are -O(CR * 2) 2-3 O-, wherein each independently occurring R * is selected from hydrogen, C 1-6 aliphatic or an unsubstituted 5- or 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0043] When R * is C 1-6 aliphatic, R * is optionally substituted by halogen, -R ● , -(halogenated R ● ), -OH, -OR ● , -O(halogenated R ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2 or -NO2, wherein each R ● is independently selected from C 1-4 aliphatic, -CH2Ph, -O(CH2) 0-1 Ph or a 5- or 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, and wherein each R ● is unsubstituted or, in the presence of a halogen group in front, is substituted only by one or more halogens.

[0044] The optional substituents that can substitute on nitrogen are independently or where each is independently hydrogen, C 1-6 aliphatic, unsubstituted -OPh or unsubstituted 5- or 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or two independently occurring together with one or more of their intervening atoms form an unsubstituted 3- to 12-membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; where when is C 1-6 aliphatic, optionally substituted with halogen, -R ● , -(haloalkyl R ● ), -OH, -OR ● , -O(haloalkyl R ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2 or -NO2, where each R ● is independently selected from C 1-4 aliphatic, -CH2Ph, -O(CH2) 0-1 Ph or a 5- or 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, and where each R ● is unsubstituted or, in the presence of a halo group in front, substituted only with one or more halogens.

[0045] As used herein, the term "pharmaceutically acceptable salts" refers to those salts that are suitable, within the scope of sound medical judgment, for contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and that are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in detail by S.M. Berge et al. in J. Pharmaceutical Sciences, 1977, 66, 1-19 (incorporated herein by reference). Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed by reacting the amino groups with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or salts formed by using other methods conventional in the art (such as ion exchange). Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptanoates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxyethanesulfonates, lactates, lactobionates, laurates, laurylsulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectates, persulfates, 3-phenylpropionates, phosphates, pivalates, propionates, stearates, succinates, sulfates, tartrates, thiocyanates, tosylates, undecanoates, valerates, etc.

[0046] In addition, acids generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al., Camille G. (ed.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al., Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33201 - 217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; and The Orange Book (Food & Drug Administration, Washington, D.C. on its website). These disclosures are incorporated herein by reference.

[0047] Salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and N + (C 1-4 (alkyl)4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium salts, etc. Where appropriate, other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide ions, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0048] Unless otherwise specified, the structures depicted herein are also intended to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations at each asymmetric center, the Z and E double bond isomers, and the Z and E conformational isomers. Thus, the individual stereochemical isomers of the compounds of the invention, as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures, are within the scope of the invention. Unless otherwise specified, all tautomeric forms of the compounds of the invention are within the scope of the invention. The invention includes compounds that differ only in the presence of one or more isotopically enriched atoms. By way of example, compounds having the structure of the invention and including hydrogen replaced by deuterium or tritium or carbon replaced by 13 C or 14 C-enriched carbon are within the scope of the invention. Such compounds can be used, for example, as analytical tools, probes in biological assays, or therapeutic agents according to the invention.

[0049] The diastereomeric mixtures can be separated into their individual diastereoisomers based on their physicochemical differences by methods known to those skilled in the art, such as by chromatography and / or fractional crystallization. The enantiomeric mixtures can be converted into diastereomeric mixtures by reacting them with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereoisomers and converting the individual diastereoisomers (e.g., by hydrolysis) into the corresponding pure enantiomers to separate the enantiomers. Alternatively, the specific enantiomers of the compounds of the present invention can be prepared by asymmetric synthesis. In addition, in the case where the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxylic acid group), diastereomeric salts are formed with a suitable optically active acid or base, and then the diastereoisomers thus formed are resolved by fractional crystallization or chromatography known in the art, and subsequently the pure enantiomers are recovered.

[0050] The individual stereoisomers of the compounds of the present invention can, for example, be substantially free of other isomers, or can, for example, be mixed as a racemate or with all other or other selected stereoisomers. One or more chiral centers in the compounds of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. In addition, insofar as the compounds described herein can exist as atropisomers (e.g., substituted biaryls), all forms of such atropisomers are considered to be part of the present invention.

[0051] The chemical name, common name and chemical structure can be used interchangeably to describe the same structure. If both the chemical structure and the chemical name are used to refer to a chemical compound and there is an ambiguity between the structure and the name, the structure shall prevail. It should also be noted that any carbon and heteroatom with an unsatisfied valence in the text, process, examples and tables herein are assumed to have a sufficient number of one or more hydrogen atoms to satisfy the valence.

[0052] Unless the context is inappropriate, as used herein, the terms "a" and "an" mean "one or more (species)" and include the plural.

[0053] The term "alkyl" refers to a saturated straight-chain or branched-chain hydrocarbon, such as a straight-chain or branched-chain group having 1-12, 1-10 or 1-6 carbon atoms, which are referred to herein as C1-C 12 alkyl, C1-C 10Alkyl and C1-C6 alkyl. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, and the like.

[0054] The term "cycloalkyl" refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group having 3-12, 3-8, 4-8, or 4-6 carbons, referred to herein as, for example, "C3-C6 cycloalkyl" derived from cycloalkanes. Exemplary cycloalkyl groups include cyclohexyl, cyclopentyl, cyclobutyl, and cyclopropyl. The term "cycloalkylene" refers to a divalent cycloalkyl group.

[0055] The term "haloalkyl" refers to an alkyl group substituted with at least one halogen. Exemplary haloalkyl groups include -CH2F, -CHF2, -CF3, -CH2CF3, -CF2CF3, and the like. The term "chloroalkyl" refers to an alkyl group substituted with at least one chlorine. The term "bromoalkyl" refers to an alkyl group substituted with at least one bromine. The term "haloalkylene" refers to a divalent haloalkyl group.

[0056] The term "hydroxyalkyl" refers to an alkyl group substituted with at least one hydroxy group. Exemplary hydroxyalkyl groups include -CH2CH2OH, -C(H)(OH)CH3, -CH2C(H)(OH)CH2CH2OH, and the like.

[0057] The term "heteroalkyl" refers to an alkyl group in which one or more carbon atoms are replaced by heteroatoms (e.g., N, O, or S). Exemplary heteroalkyl groups include -OCH3, -CH2OCH3, -CH2CH2N(CH3)2, and -CH2CH2OH. Heteroalkyl groups can contain, for example, 2-4, 2-6, or 2-8 atoms selected from the group consisting of carbon and heteroatoms (e.g., N, O, or S). The phrase "3-8 membered heteroalkyl" refers to a heteroalkyl group having 3 to 8 atoms selected from the group consisting of carbon and heteroatoms. The term "heteroalkylene" refers to a divalent heteroalkyl group.

[0058] The terms "alkenyl" and "alkynyl" are well recognized in the art and refer to unsaturated aliphatic groups of a length and possible substitution similar to those described above for alkyl, but containing at least one double bond or triple bond, respectively. The term "haloalkenyl" refers to an alkenyl group substituted with at least one halogen. The term "fluoroalkenyl" refers to an alkenyl group substituted with at least one fluorine. The term "nitroalkenyl" refers to an alkenyl group substituted with at least one nitro group.

[0059] The term "subcarbocyclic group" refers to a divalent alicyclic group.

[0060] The term "alkoxyl" or "alkoxy" is well - recognized in the art and refers to an alkyl group as defined above having an oxygen group attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propoxy, tert - butoxy, etc. The term "haloalkoxyl" refers to an alkoxyl group substituted with at least one halogen. Exemplary haloalkoxyl groups include -OCH2F, -OCHF2, -OCF3, -OCH2CF3, -OCF2CF3, etc.

[0061] The term "oxo" is well - recognized in the art and refers to the "=O" substituent. For example, cyclopentane substituted with an oxo group is cyclopentanone.

[0062] The term "amino" is well - recognized in the art and refers to unsubstituted and substituted amines, for example, a moiety represented by the following general formula:

[0063]

[0064] wherein R 50 、R 51 、R 52 and R 53 each independently represents hydrogen, alkyl, alkenyl, -(CH2) m -R 61 ,or R 50 and R 51 together with the N atom to which they are attached form a heterocycle having 4 to 8 atoms in the ring structure; R 61 represents aryl, 3 - 7 - membered cycloalkyl, 4 - 7 - membered cycloalkenyl, 5 - 10 - membered heteroaryl or 3 - 10 - membered heterocyclic group; and m is 0 or an integer in the range of 1 to 8.

[0065] The term "amido" is well - recognized in the art and refers to unsubstituted and substituted amides, for example, a moiety represented by the following general formula:

[0066]

[0067] wherein R 50 and R 51 each independently represents hydrogen, alkyl, alkenyl, -(CH2) m -R 61 ,or R 50 and R 51 together with the N atom to which they are attached form a heterocycle having 4 to 8 atoms in the ring structure; R 61represents aryl, 3-7 membered cycloalkyl, 4-7 membered cycloalkenyl, 5-10 membered heteroaryl or 3-10 membered heterocyclic group; and m is 0 or an integer in the range of 1 to 8; and R 52 is alkyl, alkenyl or -(CH2) m -R 61 .

[0068] The symbol indicates the point of attachment.

[0069] Unless otherwise indicated, when any substituent or variable occurs more than once in any component or the compounds of the present invention, its definition at each occurrence is independent of its definition at each other occurrence.

[0070] One or more compounds of the present invention may exist in unsolvated and solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc., and the present invention is intended to cover both solvated and unsolvated forms. "Solvate" means the physical association of a compound of the present invention with one or more solvent molecules. Such physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, the solvate will be capable of separation, for example, when one or more solvent molecules are incorporated into the lattice of a crystalline solid. "Solvate" encompasses solution phase and separable solvates. Non-limiting examples of suitable solvates include alcoholates, methanolates, etc. "Hydrate" is a solvate in which the solvent molecule is H2O.

[0071] As used herein, the terms "subject" and "patient" are used interchangeably and refer to an organism to be treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., mouse, monkey, horse, cow, pig, dog, cat, etc.), and most preferably include humans.

[0072] The term "IC 50 " is well recognized in the art and refers to the concentration of a compound required to achieve 50% inhibition of a target.

[0073] As used herein, the term "effective amount" means an amount of a compound sufficient to achieve a beneficial or desired result (e.g., a therapeutic, ameliorating, inhibitory or prophylactic result). The effective amount may be administered in one or more administrations, applications or doses and is not intended to be limited to a particular formulation or route of administration. As used herein, the term "treatment" includes any action that causes an improvement in a disorder, disease, condition, etc., e.g., alleviating, reducing, modulating, ameliorating or eliminating, or improving its symptoms.

[0074] As used herein, the term "pharmaceutical composition" refers to a combination of an active agent with an inert or active carrier such that the composition is particularly suitable for in vivo or ex vivo diagnostic or therapeutic use.

[0075] As used herein, the term "pharmaceutically acceptable carrier" refers to any of the standard pharmaceutical carriers, such as phosphate buffered saline solutions, water, emulsions (such as oil / water or water / oil emulsions), and various types of wetting agents. The compositions may also contain stabilizers and preservatives. For examples of carriers, stabilizers, and adjuvants, see, for example, Martin, Remington's Pharmaceutical Sciences, 15th ed., Mack Publ. Co., Easton, PA

[1975] .

[0076] For therapeutic use, salts of the compounds of the invention are expected to be pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable acids and bases may also be used, for example, in the preparation or purification of pharmaceutically acceptable compounds.

[0077] In addition, when the compounds of the invention contain a basic moiety (such as, but not limited to, pyridine or imidazole) and an acidic moiety (such as, but not limited to, carboxylic acid), zwitterions ("inner salts") can be formed. Such acidic and basic salts used within the scope of the invention are pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts. Such salts of the compounds of the invention can be formed, for example, by reacting the compounds of the invention with an amount (such as an equivalent amount) of an acid or base in a medium (such as a medium in which the salt precipitates) or in an aqueous medium, followed by lyophilization.

[0078] Throughout the description, where a composition is described as having, including, or containing a particular component, or where a process and method are described as having, including, or containing a particular step, it is also contemplated that the compositions of the invention consist essentially of or consist of the recited components, and that the processes and methods according to the invention consist essentially of or consist of the recited processing steps.

[0079] Generally, unless otherwise indicated, percentages of compositions are by weight.

[0080] I. Heterobifunctional Compounds

[0081] One aspect of the invention provides heterobifunctional compounds. The compounds can be used in the pharmaceutical compositions and therapeutic methods described herein. Exemplary compounds, together with exemplary procedures for preparing the compounds, are described in the following sections. Without being bound by theory, the compounds may promote therapeutic effects by binding to both the androgen receptor and BRD4 (bromodomain-containing protein 4).

[0082] Part A: Compounds of Formula I

[0083] One aspect of the invention provides a compound represented by Formula I:

[0084]

[0085] or a pharmaceutically acceptable salt thereof; wherein:

[0086] R 1 is phenyl substituted with cyano, halogen, and m occurrences of R 4 substituents;

[0087] R 2 and R 3 are independently hydrogen or C 1-4 alkyl;

[0088] R 4 is C 1-4 alkyl;

[0089] R 5 independently represents C 1-4 alkyl or halogen at each occurrence;

[0090] A 1 is pyridazin-1-yl, pyrimidin-1-yl, pyrazin-1-yl, pyridin-1-yl, or phenyl, each of which is substituted with n occurrences of R 5 substituents;

[0091] L is a linker; and

[0092] A 2 is one of the following:

[0093]

[0094] R 1A is C 1-4 alkyl or C 3-4 cycloalkyl;

[0095] R 2A independently represents C 1-4 alkyl or C 3-4 cycloalkyl at each occurrence;

[0096] R 3A is phenyl substituted with 1, 2, or 3 substituents independently selected from halo, C1-C4 alkyl, or C1-C4 haloalkyl;

[0097] R 4A is -(C 1-6 alkylene)-C(O)N(R 5A )(R 6A ), -(C 1-6 alkylene)-N(R 5A )C(O)R 7A 1-6 7A 1-6 7A is -(C 1-6 alkylene)-CO2R 7A 1-6 is -(C 1-6 alkylene)-OC(O)R7A or -(C 0-6 alkylene)-(5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur), -(C 1-6 alkylene)-cyano, C 1-6 alkyl or hydrogen; or R 4A and R 10A together with the carbon atom to which they are attached form a C 3-5 saturated carbocycle;

[0098] R 5A and R 6A are independently hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl; or R 5A and R 6A together with the nitrogen atom to which they are attached form a 3- to 7-membered ring containing 1 nitrogen atom;

[0099] R 7A is C 1-6 alkyl, -(C 1-6 alkylene)-(C 3-6 cycloalkyl) or C 3-6 cycloalkyl;

[0100] R 8A independently represents C 1-4 alkyl or -N(R 9A )2 each time it appears;

[0101] R 9A independently represents hydrogen or C 1-4 alkyl each time it appears;

[0102] R 10A is hydrogen or C 1-4 alkyl; and

[0103] m, n, p and q are independently 0, 1 or 2.

[0104] The definitions of the variables in Formula I above encompass multiple chemical groups. This application covers the following embodiments. For example, i) the definition of the variable is a single chemical group selected from those chemical groups set forth above, ii) the definition of the variable is a set of two or more of those chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables defined by (i) or (ii).

[0105] In certain embodiments, the compound is a compound of Formula I.

[0106] As generally defined above, R 1 is substituted with cyano, halogen and m occurrences of R 4Substituted phenyl. In certain embodiments, R 1 is phenyl substituted with cyano, halogen, and zero occurrences of R 4 Substituted phenyl. In certain embodiments, R 1 is phenyl substituted with cyano, halogen, and one occurrence of R 4 Substituted phenyl. In certain embodiments, R 1 is phenyl substituted with cyano, halogen, and two occurrences of R 4 Substituted phenyl. In certain embodiments, R 1 is phenyl substituted with cyano, Cl, and zero occurrences of R 4 Substituted phenyl. In certain embodiments, R 1 is In certain embodiments, R 1 is a group depicted in the compounds of Table 1 below.

[0107] As generally defined above, R 2 is hydrogen or C 1-4 alkyl. In certain embodiments, R 2 is hydrogen. In certain embodiments, R 2 is C 1-4 alkyl. In certain embodiments, R 2 is a group depicted in the compounds of Table 1 below.

[0108] As generally defined above, R 3 is hydrogen or C 1-4 alkyl. In certain embodiments, R 3 is hydrogen. In certain embodiments, R 3 is C 1-4 alkyl. In certain embodiments, R 3 is a group depicted in the compounds of Table 1 below.

[0109] As generally defined above, A 1 is pyridazinylene, pyrimidinylene, pyrazinylene, pyridinylene, or phenylene, each of which is substituted with n occurrences of R 5 Substituted. In certain embodiments, A 1 is pyridazinylene substituted with n occurrences of R 5 Substituted. In certain embodiments, A 1 is In certain embodiments, A 1 is pyrimidinylene substituted with n occurrences of R 5 Substituted. In certain embodiments, A 1 is where ** is the point of attachment to L. In certain embodiments, A 1 is where ** is the connection point to L. In certain embodiments, A 1 is a pyridazine group substituted with R 5 appearing n times. In certain embodiments, A 1 is In certain embodiments, A 1 is a pyridine group substituted with R 5 appearing n times. In certain embodiments, A 1 is where ** is the connection point to L. In certain embodiments, A 1 is a phenyl group substituted with R 5 appearing n times. In certain embodiments, A 1 is In certain embodiments, A 1 is a pyridazine group substituted with R 5 appearing 0 times. In certain embodiments, A 1 is a pyrimidine group substituted with R 5 appearing 0 times. In certain embodiments, A 1 is a pyridazine group substituted with R 5 appearing 0 times. In certain embodiments, A 1 is a pyridine group substituted with R 5 appearing 0 times. In certain embodiments, A 1 is a phenyl group substituted with R 5 appearing 0 times. In certain embodiments, A 1 is selected from the groups depicted in the compounds of Table 1 below.

[0110] As generally defined above, A 2 is In certain embodiments, A 2 is In certain embodiments, A 2 is In certain embodiments, A 2 is In certain embodiments, A 2 is In certain embodiments, A 2 is In certain embodiments, A 2 is In certain embodiments, A 2 is In certain embodiments, A 2 is In certain embodiments, A 2 is

[0111] In certain embodiments, A 2 is In certain embodiments, A 2 is In certain embodiments, A 2 is In certain embodiments, A 2 is In certain embodiments, A 2 is In certain embodiments, A 2 is In certain embodiments, A 2 is In certain embodiments, A 2 is In certain embodiments, A 2 is In certain embodiments, A 2 is In certain embodiments, A 2 is In certain embodiments, A 2 is In certain embodiments, A 2 is

[0112] In certain embodiments, A 2 is selected from the groups depicted in the compounds of Table 1 below.

[0113] As generally defined above, R 1A is C 1-4 alkyl or C 3-4 cycloalkyl. In certain embodiments, R 1A is C 1-4 alkyl. In certain embodiments, it is methyl. In certain embodiments, R 1A is C 3-4 cycloalkyl. In certain embodiments, R 1A is selected from the groups depicted in the compounds of Table 1 below.

[0114] As generally defined above, R 2A independently represents C 1-4 alkyl or C 3-4 cycloalkyl each time it appears. In certain embodiments, R 2A is C 1-4 alkyl. In certain embodiments, R2A is methyl. In certain embodiments, R 2A is C 3-4 cycloalkyl. In certain embodiments, R 2A is selected from the groups depicted in the compounds of Table 1 below.

[0115] As generally defined above, R 3A is phenylhalo, C1-C4 alkyl or C1-C4 haloalkyl substituted with 1, 2 or 3 substituents independently selected from. In certain embodiments, R 3A is phenyl substituted with halo. In certain embodiments, R 3A is phenyl substituted with 1 substituent selected from halo, C1-C4 alkyl or C1-C4 haloalkyl. In certain embodiments, R 3A is phenyl substituted with 2 substituents independently selected from halo, C1-C4 alkyl or C1-C4 haloalkyl. In certain embodiments, R 3A is phenyl substituted with 3 substituents independently selected from halo, C1-C4 alkyl or C1-C4 haloalkyl. In certain embodiments, R 3A is selected from the groups depicted in the compounds of Table 1 below.

[0116] As generally defined above, R 4A is -(C 1-6 alkylene)-C(O)N(R 5A )(R 6A ), -(C 1-6 alkylene)-N(R 5A )C(O)R 7A ), -(C 1-6 alkylene)-CO2R 7A ), -(C 1-6 alkylene)-OC(O)R 7A ), -(C 0-6 alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur), -(C 1-6 alkylene)-cyano, C 1-6 alkyl or hydrogen; or R 4A and R 10A together with the carbon atom to which they are attached form a C 3-5 saturated carbocyclic ring. In certain embodiments, R 4A is -(C 1-6 alkylene)-C(O)N(R 5A )(R 6A ), -(C 1-6 alkylene)-N(R 5A )C(O)R 7A ), -(C 1-6Alkylene)-CO2R 7A 、-(C 1-6 Alkylene)-OC(O)R 7A or -(C 0-6 In certain embodiments, R 4A Yes-(C 1-6 Alkylene)-C(O)N(R 5A )(R 6A )、-(C 1-6 Alkylene)-N(R 5A )C(O)R 7A 、-(C 1-6 Alkylene)-CO2R 7A or -(C 1-6 Alkylene)-OC(O)R 7A In certain embodiments, R 4A is hydrogen. In certain embodiments, R 4A Yes-(C 1-6 In certain embodiments, R 4A It is C 1-6 In certain embodiments, R 4A Yes-(C 1-6 Alkylene)-C(O)N(R 5A )(R 6A In certain embodiments, R 4A Yes-(C 1-6 Alkylene)-CO2R 7A In certain embodiments, R 4A Yes-(C 1-6 Alkylene)-N(R 5A )C(O)R 7A In certain embodiments, R 4A Yes-(C 1-6 Alkylene)-OC(O)R 7A In certain embodiments, R 4A Yes-(C 0-6 In certain embodiments, R 4A and R 10A Together with the carbon atom to which they are attached, they form C 3-5 In certain embodiments, R 4A A group selected from the compounds depicted in Table 1 below.

[0117] As generally defined above, R 5A and R 6AIndependently is hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl; or R 5A and R 6A together with the nitrogen atom to which they are attached form a 3- to 7-membered ring containing 1 nitrogen atom. In certain embodiments, R 5A and R 6A independently are hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl. In certain embodiments, R 5A is hydrogen. In certain embodiments, R 5A is C 1-6 alkyl. In certain embodiments, R 5A is C 3-6 cycloalkyl. In certain embodiments, R 6A is hydrogen. In certain embodiments, R 6A is C 1-6 alkyl. In certain embodiments, R 6A is C 3-6 cycloalkyl. In certain embodiments, R 5A and R 6A together with the nitrogen atom to which they are attached form a 3- to 7-membered ring containing 1 nitrogen atom. In certain embodiments, R 5A and R 6A together with the nitrogen atom to which they are attached form a 3-membered ring containing 1 nitrogen atom. In certain embodiments, R 5A and R 6A together with the nitrogen atom to which they are attached form a 4-membered ring containing 1 nitrogen atom. In certain embodiments, R 5A and R 6A together with the nitrogen atom to which they are attached form a 5-membered ring containing 1 nitrogen atom. In certain embodiments, R 5A and R 6A together with the nitrogen atom to which they are attached form a 6-membered ring containing 1 nitrogen atom. In certain embodiments, R 5A and R 6A together with the nitrogen atom to which they are attached form a 7-membered ring containing 1 nitrogen atom. In certain embodiments, R 5A is selected from the groups depicted in the compounds of Table 1 below. In certain embodiments, R 6A is selected from the groups depicted in the compounds of Table 1 below.

[0118] As generally defined above, R 7A is C 1-6 alkyl, -(C 1-6 alkylene)-(C 3-6 cycloalkyl) or C 3-6 cycloalkyl. In certain embodiments, R7A is C 1-6 alkyl. In certain embodiments, R 7A is -(C 1-6 alkylene)-(C 3-6 cycloalkyl). In certain embodiments, R 7A is C 3-6 cycloalkyl. In certain embodiments, R 7A is selected from the groups depicted in the compounds of Table 1 below.

[0119] As generally defined above, R 8A independently represents C 1-4 alkyl or -N(R 9A )2 each time it appears. In certain embodiments, R 8A independently represents C 1-4 alkyl each time it appears. In certain embodiments, R 8A independently represents -N(R 9A )2 each time it appears. In certain embodiments, R 8A is C 1-4 alkyl. In certain embodiments, R 8A is -N(R 9A )2. In certain embodiments, R 8A is -N(H)CH3. In certain embodiments, R 8A is selected from the groups depicted in the compounds of Table 1 below.

[0120] As generally defined above, R 9A independently represents hydrogen or C 1-4 alkyl each time it appears. In certain embodiments, R 9A independently represents C 1-4 alkyl each time it appears. In certain embodiments, R 9A is hydrogen. In certain embodiments, R 9A is C 1-4 alkyl. In certain embodiments, R 9A independently represents hydrogen or methyl each time it appears. In certain embodiments, R 9A is selected from the groups depicted in the compounds of Table 1 below.

[0121] As generally defined above, R 10A is hydrogen or C 1-4 alkyl. In certain embodiments, R 10A is hydrogen. In certain embodiments, R 10A is C 1-4 alkyl. In certain embodiments, R 10A is methyl. In certain embodiments, R 10AGroups depicted in the compounds selected from Table 1 below.

[0122] As generally defined above, m, n, and p are independently 0, 1, or 2. In certain embodiments, p is 2. In certain embodiments, p is 1. In certain embodiments, p is 0. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, q is 0. In certain embodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, p is selected from the corresponding values of the groups depicted in the compounds of Table 1 below. In certain embodiments, m is selected from the corresponding values of the groups depicted in the compounds of Table 1 below. In certain embodiments, n is selected from the corresponding values of the groups depicted in the compounds of Table 1 below.

[0123] In certain embodiments, the compound of formula I is further defined by formula Ia or formula Ib or a pharmaceutically acceptable salt thereof:

[0124]

[0125] In certain embodiments, the variable R 1 、R 2 、R 3 、A 1 and A 2 are defined as one of the embodiments described above in connection with formula I. In certain embodiments, the compound is a compound of formula Ia or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of formula Ib or a pharmaceutically acceptable salt thereof.

[0126] In certain embodiments, the compound of formula I is further defined by formula 1c or a pharmaceutically acceptable salt thereof:

[0127]

[0128] In certain embodiments, the variables A 1 and A 2 are defined as one of the embodiments described above in connection with formula I.

[0129] In certain embodiments, the compound of formula I is further defined by formula 1d or a pharmaceutically acceptable salt thereof:

[0130]

[0131] In certain embodiments, the variables A 1 and A 2 are defined as one of the embodiments described above in connection with formula I.

[0132] The compounds can be further characterized, for example, according to the identity of L. Exemplary further embodiments of L are provided in Part C below.

[0133] Part A-1: Compounds of Formula I-1

[0134] One aspect of the present invention provides a compound represented by Formula I-1:

[0135]

[0136] or a pharmaceutically acceptable salt thereof; wherein:

[0137] R 1 is phenyl substituted with cyano, halogen, and m occurrences of R 4 ;

[0138] R 2 and R 3 are independently hydrogen or C 1-4 alkyl;

[0139] R 4 is C 1-4 alkyl;

[0140] R 5 independently represents C 1-4 alkyl or halogen at each occurrence;

[0141] A 1 is pyridazinylene, pyrimidinylene, pyrazinylene, pyridinylene, or phenylene, each of which is substituted with n occurrences of R 5 ;

[0142] L is a linker; and

[0143] A 2 is one of the following:

[0144]

[0145] R 1A is C 1-4 alkyl or C 3-4 cycloalkyl;

[0146] R 2A independently represents C 1-4 alkyl or C 3-4 cycloalkyl at each occurrence;

[0147] R 3A is phenyl substituted with 1, 2, or 3 substituents independently selected from halo, C1-C4 alkyl, or C1-C4 haloalkyl;

[0148] R 4A is -(C 1-6(alkylene)-C(O)N(R 5A )(R 6A )、-(C 1-6 alkylene)-N(R 5A )C(O)R 7A 、-(C 1-6 alkylene)-CO2R 7A 、-(C 1-6 alkylene)-OC(O)R 7A or -(C 0-6 alkylene)-(5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur);

[0149] R 5A and R 6A are independently hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl; or R 5A and R 6A together with the nitrogen atom to which they are attached form a 3- to 7-membered ring containing 1 nitrogen atom;

[0150] R 7A is C 1-6 alkyl, -(C 1-6 alkylene)-(C 3-6 cycloalkyl) or C 3-6 cycloalkyl; and

[0151] m, n and p are independently 0, 1 or 2.

[0152] The definitions of the variables in Formula I-1 above encompass multiple chemical groups. This application covers the following embodiments. For example, i) the definition of the variable is a single chemical group selected from those chemical groups set forth above, ii) the definition of the variable is a collection of two or more of those chemical groups set forth above, and iii) the compound is defined by a combination of variables defined by (i) or (ii).

[0153] In certain embodiments, the compound is a compound of Formula I-1.

[0154] As generally defined above, R 1 is phenyl substituted with cyano, halogen and m occurrences of R 4 . In certain embodiments, R 1 is phenyl substituted with cyano, halogen and 0 occurrences of R 4 . In certain embodiments, R 1 is phenyl substituted with cyano, halogen and 1 occurrence of R 4 . In certain embodiments, R 1 is phenyl substituted with cyano, halogen and 2 occurrences of R 4Substituted phenyl. In certain embodiments, R 1 is phenyl substituted with cyano, Cl, and zero occurrences of R 4 Substituted phenyl. In certain embodiments, R 1 is In certain embodiments, R 1 is a group depicted in the compounds of Table 1 below.

[0155] As generally defined above, R 2 is hydrogen or C 1-4 alkyl. In certain embodiments, R 2 is hydrogen. In certain embodiments, R 2 is C 1-4 alkyl. In certain embodiments, R 2 is a group depicted in the compounds of Table 1 below.

[0156] As generally defined above, R 3 is hydrogen or C 1-4 alkyl. In certain embodiments, R 3 is hydrogen. In certain embodiments, R 3 is C 1-4 alkyl. In certain embodiments, R 3 is a group depicted in the compounds of Table 1 below.

[0157] As generally defined above, A 1 is a pyridazinylene, pyrimidinylene, pyrazinylene, pyridinylene, or phenylene group, each of which is substituted with n occurrences of R 5 In certain embodiments, A 1 is pyridazinylene substituted with n occurrences of R 5 In certain embodiments, A 1 is In certain embodiments, A 1 is pyrimidinylene substituted with n occurrences of R 5 In certain embodiments, A 1 is where ** is the point of attachment to L. In certain embodiments, A 1 is where ** is the point of attachment to L. In certain embodiments, A 1 is pyrazinylene substituted with n occurrences of R 5 In certain embodiments, A 1 is In certain embodiments, A 1 is pyridinylene substituted with n occurrences of R 5 In certain embodiments, A 1 is wherein ** is the connection point with L. In certain embodiments, A 1 is a phenylene group substituted by n occurrences of R 5 In certain embodiments, A 1 is In certain embodiments, A 1 is a pyridazinyl group substituted by 0 occurrences of R 5 In certain embodiments, A 1 is a pyrimidinyl group substituted by 0 occurrences of R 5 In certain embodiments, A 1 is a pyrazinyl group substituted by 0 occurrences of R 5 In certain embodiments, A 1 is a pyridinyl group substituted by 0 occurrences of R 5 In certain embodiments, A 1 is a phenylene group substituted by 0 occurrences of R 5 In certain embodiments, A 1 is selected from the groups depicted in the compounds of Table 1 below.

[0158] As generally defined above, A 2 is

[0159] In certain embodiments, A 2 is In certain embodiments, A 2 is In certain embodiments, A 2 is In certain embodiments, A 2 is In certain embodiments, A 2 is In certain embodiments, A 2 is selected from the groups depicted in the compounds of Table 1 below.

[0160] As generally defined above, R 1A is C 1-4 alkyl or C 3-4 cycloalkyl. In certain embodiments, R 1A is C 1-4 alkyl. In certain embodiments, it is methyl. In certain embodiments, R 1A is C 3-4 cycloalkyl. In certain embodiments, R 1A is selected from the groups depicted in the compounds of Table 1 below.

[0161] As generally defined above, R2A independently represents C at each occurrence 1-4 alkyl or C 3-4 cycloalkyl. In certain embodiments, R 2A is C 1-4 alkyl. In certain embodiments, R 2A is methyl. In certain embodiments, R 2A is C 3-4 cycloalkyl. In certain embodiments, R 2A is selected from the groups depicted in the compounds of Table 1 below.

[0162] As generally defined above, R 3A is phenylhalo, C1-C4 alkyl or C1-C4 haloalkyl substituted with 1, 2 or 3 substituents independently selected from. In certain embodiments, R 3A is phenyl substituted with a halo group. In certain embodiments, R 3A is phenyl substituted with 1 substituent selected from halo, C1-C4 alkyl or C1-C4 haloalkyl. In certain embodiments, R 3A is phenyl substituted with 2 substituents independently selected from halo, C1-C4 alkyl or C1-C4 haloalkyl. In certain embodiments, R 3A is phenyl substituted with 3 substituents independently selected from halo, C1-C4 alkyl or C1-C4 haloalkyl. In certain embodiments, R 3A is selected from the groups depicted in the compounds of Table 1 below.

[0163] As generally defined above, R 4A is -(C 1-6 alkylene)-C(O)N(R 5A )(R 6A ), -(C 1-6 alkylene)-N(R 5A )C(O)R 7A 、-(C 1-6 alkylene)-CO2R 7A 、-(C 1-6 alkylene)-OC(O)R 7A or -(C 0-6 alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur). In certain embodiments, R 4A is -(C 1-6 alkylene)-C(O)N(R 5A )(R 6A ), -(C 1-6 alkylene)-N(R 5A )C(O)R 7A 、-(C1-6 -(alkylene)-CO2R 7A or -(C 1-6 alkylene)-OC(O)R 7A . In certain embodiments, R 4A is -(C 1-6 alkylene)-C(O)N(R 5A )(R 6A ). In certain embodiments, R 4A is -(C 1-6 alkylene)-CO2R 7A . In certain embodiments, R 4A is -(C 1-6 alkylene)-N(R 5A )C(O)R 7A . In certain embodiments, R 4A is -(C 1-6 alkylene)-OC(O)R 7A . In certain embodiments, R 4A is -(C 0-6 alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur). In certain embodiments, R 4A is selected from the groups depicted in the compounds of Table 1 below.

[0164] As generally defined above, R 5A and R 6A are independently hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl; or R 5A and R 6A together with the nitrogen atom to which they are attached form a 3-7 membered ring containing 1 nitrogen atom. In certain embodiments, R 5A and R 6A are independently hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl. In certain embodiments, R 5A is hydrogen. In certain embodiments, R 5A is C 1-6 alkyl. In certain embodiments, R 5A is C 3-6 cycloalkyl. In certain embodiments, R 6A is hydrogen. In certain embodiments, R 6A is C 1-6 alkyl. In certain embodiments, R 6A is C 3-6 cycloalkyl. In certain embodiments, R 5A and R 6ATogether with the nitrogen atom to which they are attached, form a 3- to 7-membered ring containing one nitrogen atom. In certain embodiments, R 5A and R 6A Together with the nitrogen atom to which they are attached, form a 3-membered ring containing one nitrogen atom. In certain embodiments, R 5A and R 6A Together with the nitrogen atom to which they are attached, form a 4-membered ring containing one nitrogen atom. In certain embodiments, R 5A and R 6A Together with the nitrogen atom to which they are attached, form a 5-membered ring containing one nitrogen atom. In certain embodiments, R 5A and R 6A Together with the nitrogen atom to which they are attached, form a 6-membered ring containing one nitrogen atom. In certain embodiments, R 5A and R 6A Together with the nitrogen atom to which they are attached, form a 7-membered ring containing one nitrogen atom. In certain embodiments, R 5A is selected from the groups depicted in the compounds of Table 1 below. In certain embodiments, R 6A is selected from the groups depicted in the compounds of Table 1 below.

[0165] As generally defined above, R 7A is C 1-6 alkyl, -(C 1-6 alkylene)-(C 3-6 cycloalkyl) or C 3-6 cycloalkyl. In certain embodiments, R 7A is C 1-6 alkyl. In certain embodiments, R 7A is -(C 1-6 alkylene)-(C 3-6 cycloalkyl). In certain embodiments, R 7A is C 3-6 cycloalkyl. In certain embodiments, R 7A is selected from the groups depicted in the compounds of Table 1 below.

[0166] As generally defined above, m, n, and p are independently 0, 1, or 2. In certain embodiments, p is 2. In certain embodiments, p is 1. In certain embodiments, p is 0. In certain embodiments, t is 2. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, p is selected from the corresponding values of the groups depicted in the compounds of Table 1 below. In certain embodiments, m is selected from the corresponding values of the groups depicted in the compounds of Table 1 below. In certain embodiments, n is selected from the corresponding values of the groups depicted in the compounds of Table 1 below.

[0167] In certain embodiments, the compound of formula I-1 is further defined by formula Ia or formula Ib or a pharmaceutically acceptable salt thereof:

[0168]

[0169] In certain embodiments, the variable R 1 、R 2 、R 3 、A 1 and A 2 are defined as one of the embodiments described above in connection with formula I-1. In certain embodiments, the compound is a compound of formula Ia-1 or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of formula Ib-1 or a pharmaceutically acceptable salt thereof.

[0170] In certain embodiments, the compound of formula I-1 is further defined by formula 1c-1 or a pharmaceutically acceptable salt thereof:

[0171]

[0172] In certain embodiments, the variables A 1 and A 2 are defined as one of the embodiments described above in connection with formula I-1.

[0173] In certain embodiments, the compound of formula I-1 is further defined by formula 1d-1 or a pharmaceutically acceptable salt thereof:

[0174]

[0175] In certain embodiments, the variables A 1 and A 2 are defined as one of the embodiments described above in connection with formula I-1.

[0176] The compound can be further characterized, for example, according to the identity of L. Exemplary further embodiments of L are provided in Part C below.

[0177] Part A-2: Compound of Formula I*

[0178] Another aspect of the present invention provides a compound represented by Formula I*:

[0179]

[0180] or a pharmaceutically acceptable salt thereof; wherein:

[0181] R 1 is phenyl substituted with cyano, halogen and m occurrences of R 4 ;

[0182] R 2 and R 3 are independently hydrogen or C 1-4 alkyl;

[0183] R 4 is C 1-4 alkyl;

[0184] R 5 independently represents C 1-4 alkyl or halogen at each occurrence;

[0185] A 1 is pyridazinylene, pyrimidinylene, pyrazinylene, pyridinylene or phenylene, each of which is substituted with n occurrences of R 5 ;

[0186] L is a linker; and

[0187] A 2 is one of the following:

[0188]

[0189] R 1A is C 1-4 alkyl or C 3-4 cycloalkyl;

[0190] R 2A independently represents C 1-4 alkyl or C 3-4 cycloalkyl at each occurrence;

[0191] R 4A is -(C 1-6 alkylene)-O-(C 1-6 alkyl), C 1-6 hydroxyalkyl, C 1-6 haloalkyl, -(C 1-6 alkylene)-C(O)N(R 5A )(R 6A ), -(C1-6 -alkylene)-N(R 5A )C(O)R 7A -, -(C 1-6 -alkylene)-CO2R 7A -, -(C 1-6 -alkylene)-OC(O)R 7A -, -(C 0-6 -alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur), -(C 1-6 -alkylene)-cyano, C 1-6 -alkyl or hydrogen; or R 4A and R 10A together with the carbon atom to which they are attached form a C 3-5 -saturated carbocyclic ring;

[0192] R 5A and R 6A are independently hydrogen, C 1-6 -alkyl or C 3-6 -cycloalkyl; or R 5A and R 6A together with the nitrogen atom to which they are attached form a 3-7 membered ring containing 1 nitrogen atom;

[0193] R 7A is C 1-6 -alkyl, -(C 1-6 -alkylene)-(C 3-6 -cycloalkyl) or C 3-6 -cycloalkyl;

[0194] R 8A independently represents C 1-4 -alkyl or -N(R 9A )2 at each occurrence;

[0195] R 9A independently represents hydrogen or C 1-4 -alkyl at each occurrence;

[0196] R 10A is hydrogen or C 1-4 -alkyl;

[0197] R 11A independently represents halogen at each occurrence; and

[0198] m, n, p and q are independently 0, 1 or 2.

[0199] In certain embodiments, the compound is a compound of formula Ic* or a pharmaceutically acceptable salt thereof:

[0200]

[0201] In certain embodiments, the compound is a compound of formula Id* or a pharmaceutically acceptable salt thereof:

[0202]

[0203] In certain embodiments, A 1 is In certain embodiments, A 1 is where * is the point of attachment to L.

[0204] In certain embodiments, A 2 is where q is 1.

[0205] In certain embodiments, R 4A is -(C 0-6 alkylene)-(5-6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In certain embodiments, R 4A is -(C 1-6 alkylene)-O-(C 1-6 alkyl), C 1-6 hydroxyalkyl, or C 1-6 haloalkyl.

[0206] In certain embodiments, A 2 is In certain embodiments, A 2 is one of the following: In certain embodiments, A 2 is one of the following:

[0207] In certain embodiments, A 2 is In certain embodiments, A 2 is

[0208] The compound can be further characterized, for example, based on the identity of L. Exemplary further embodiments of L are provided in Part C below.

[0209] Part A-3: Compounds of Formula Ie, Formula If, and Formula Ig and Other Compounds

[0210] Another aspect of the invention provides a compound represented by formula Ie, formula If, or formula Ig or a pharmaceutically acceptable salt thereof:

[0211]

[0212]

[0213] wherein L is one of the following:

[0214] (i) a 7- to 11-membered spiro or fused bicyclic saturated heterocycle containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen;

[0215] (ii) -(a 7- to 11-membered spiro saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(C 2-4 alkynylene)-***, where *** is the point of attachment to the phenylene group in the formula; or

[0216] (iii) -N(C 1-4 alkyl)-(C 1-6 alkylene)-(a 4- to 7-membered saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen and oxygen)-***, where *** is the point of attachment to the phenylene group in the formula.

[0217] In certain embodiments, the compound is represented by formula Ih or a pharmaceutically acceptable salt thereof:

[0218]

[0219] In certain embodiments, the compound is represented by formula Ii or a pharmaceutically acceptable salt thereof:

[0220]

[0221] In certain embodiments, the compound is represented by formula Ij or a pharmaceutically acceptable salt thereof:

[0222]

[0223] In certain embodiments, the compound is represented by formula Ik or a pharmaceutically acceptable salt thereof:

[0224]

[0225] In certain embodiments, the compound is represented by formula Il or a pharmaceutically acceptable salt thereof:

[0226]

[0227] In certain embodiments, L is a 7- to 11-membered spiro or fused bicyclic saturated heterocycle containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen. In certain embodiments, L is -(a 7- to 11-membered spiro saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(C 2-4 alkynylene)-***, where *** is the point of attachment to the phenylene group in the formula. In certain embodiments, L is -N(C 1-4(alkyl)-(C 1-6 (alkylene)-(4- to 7-membered saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen and oxygen)-***, where *** is the point of attachment to the phenylene in the formula.

[0228] In certain embodiments, L is one of the following:

[0229]

[0230] where *** is the point of attachment to the phenylene in the formula.

[0231] Another aspect of the present invention provides a compound represented by formula Im, formula In, or formula Io, or a pharmaceutically acceptable salt thereof:

[0232]

[0233]

[0234] where L is one of the following:

[0235] (i) a 7- to 11-membered spiro or fused bicyclic saturated heterocycle containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen;

[0236] (ii)-(7- to 11-membered spiro saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(C 2-4 (alkynylene)-***, where *** is the point of attachment to the phenylene in the formula; or

[0237] (iii)-N(C 1-4 (alkyl)-(C 1-6 (alkylene)-(4- to 7-membered saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen and oxygen)-***, where *** is the point of attachment to the phenylene in the formula.

[0238] In certain embodiments, the compound is represented by formula Im or a pharmaceutically acceptable salt thereof:

[0239]

[0240] In certain embodiments, the compound is represented by formula In or a pharmaceutically acceptable salt thereof:

[0241]

[0242] In certain embodiments, the compound is represented by formula Io or a pharmaceutically acceptable salt thereof:

[0243]

[0244] In certain embodiments, the compound is represented by formula Ip or a pharmaceutically acceptable salt thereof:

[0245]

[0246] In certain embodiments, the compound is represented by formula Iq or a pharmaceutically acceptable salt thereof:

[0247]

[0248] In certain embodiments, L is a 7- to 11-membered spiro or fused bicyclic saturated heterocycle containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen. In certain embodiments, L is -(a 7- to 11-membered spiro saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(C 2-4 alkynylene)-***, where *** is the point of attachment to the phenylene in the formula. In certain embodiments, L is -N(C 1-4 alkyl)-(C 1-6 alkylene)-(a 4- to 7-membered saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen and oxygen)-***, where *** is the point of attachment to the phenylene in the formula.

[0249] In certain embodiments, L is one of the following:

[0250]

[0251] where *** is the point of attachment to the phenylene in the formula.

[0252] Part B: Compounds of formula II

[0253] Another aspect of the present invention provides a compound represented by formula II:

[0254]

[0255] or a pharmaceutically acceptable salt thereof; wherein:

[0256] TPL is a group defined by formula II-1, which is substituted by one occurrence of R II-1A where formula II-1 is represented by:

[0257]

[0258] or a pharmaceutically acceptable salt thereof; wherein:

[0259] R II-1A is a bond to L;

[0260] R 1 is a phenyl group substituted by cyano, halogen and m occurrences of R 4 ;

[0261] R 2 and R 3 is independently hydrogen or C 1-4 alkyl;

[0262] R 4 is C 1-4 alkyl;

[0263] R 5 independently represents C at each occurrence 1-4 alkyl or halogen;

[0264] A 1 is pyridazinyl, pyrimidinyl, pyrazinyl, pyridyl or phenyl, each of which is substituted by n occurrences of R 5 substituted;

[0265] L is a linker;

[0266] EPL is a moiety that binds to BRD4; and

[0267] m and n are independently 0, 1 or 2.

[0268] The definitions of the variables in Formula II above encompass multiple chemical groups. This application encompasses the following embodiments. For example, i) the definition of the variable is a single chemical group selected from those chemical groups set forth above, ii) the definition of the variable is a set of two or more of those chemical groups set forth above, and iii) the compound is defined by a combination of variables defined by (i) or (ii).

[0269] In certain embodiments, the compound is a compound of Formula II.

[0270] As generally defined above, R 1 is phenyl substituted by cyano, halogen and m occurrences of R 4 In certain embodiments, R 1 is phenyl substituted by cyano, halogen and 0 occurrences of R 4 In certain embodiments, R 1 is In certain embodiments, R 1 is phenyl substituted by cyano, halogen and 1 occurrence of R 4 In certain embodiments, R 1 is phenyl substituted by cyano, halogen and 2 occurrences of R 4 In certain embodiments, R 1 is phenyl substituted by cyano, Cl and 0 occurrences of R 4 In certain embodiments, R 1 is selected from the groups depicted in the compounds of Table 1 below.

[0271] As generally defined above, R 2 and R 3 are independently hydrogen or C 1-4 alkyl. In certain embodiments, R 2 is hydrogen. In certain embodiments, R 3 is hydrogen. In certain embodiments, R 2 is C 1-4 alkyl. In certain embodiments, R 3 is C 1-4 alkyl. In certain embodiments, R 2 and R 3 are each independently selected from the groups depicted in the compounds of Table 1 below. In certain embodiments, R 2 and R 3 are each independently selected from the groups depicted in the compounds of Table 1 below.

[0272] As generally defined above, A 1 is a pyridazinyl, pyrimidinyl, pyrazinyl, pyridyl or phenyl group, each of which is substituted by n occurrences of R 5 . In certain embodiments, A 1 is a pyridazinyl group substituted by n occurrences of R 5 . In certain embodiments, A 1 is a pyrimidinyl group substituted by n occurrences of R 5 . In certain embodiments, A 1 is a pyrazinyl group substituted by n occurrences of R 5 . In certain embodiments, A 1 is a pyridyl group substituted by n occurrences of R 5 . In certain embodiments, A 1 is a phenyl group substituted by n occurrences of R 5 . In certain embodiments, A 1 is selected from the groups depicted in the compounds of Table 1 below.

[0273] In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, m is selected from the corresponding values of the groups depicted in the compounds of Table 1 below. In certain embodiments, n is selected from the corresponding values of the groups depicted in the compounds of Table 1 below.

[0274] In certain embodiments, TPL is II-1A substituted by one occurrence of R

[0275] In certain embodiments, TPL is R substituted once II-1A substituted In certain embodiments, TPL is In certain embodiments, TPL is

[0276] In certain embodiments, EPL is defined by Formula II-2, which is substituted once by R II-2A where Formula II-2 is represented as follows:

[0277] where

[0278] R II-2A is a bond to L;

[0279] R 1A is C 1-4 alkyl or C 3-4 cycloalkyl;

[0280] R 2A independently represents C 1-4 alkyl or C 3-4 cycloalkyl at each occurrence;

[0281] R 3A is phenyl substituted with 1, 2, or 3 substituents independently selected from halo, C1-C4 alkyl, or C1-C4 haloalkyl;

[0282] R 4A is -(C 1-6 alkylene)-C(O)N(R 5A )(R 6A ), -(C 1-6 alkylene)-N(R 5A )C(O)R 7A ), -(C 1-6 alkylene)-CO2R 7A ), -(C 1-6 alkylene)-OC(O)R 7A ), or -(C 0-6 alkylene)-(5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur);

[0283] R 5A and R 6A are independently hydrogen, C 1-6 alkyl, or C 3-6 cycloalkyl; or R 5A and R 6A together with the nitrogen atom to which they are attached form a 3-7 membered ring containing 1 nitrogen atom;

[0284] R 7Ais C 1-6 alkyl, -(C 1-6 alkylene)-(C 3-6 cycloalkyl) or C 3-6 cycloalkyl; and

[0285] p is 0, 1 or 2.

[0286] In certain embodiments, EPL is defined by Formula II-2, which is substituted by one occurrence of R II-2A where Formula II-2 is represented as follows:

[0287]

[0288] where

[0289] R II-2A is a bond to L;

[0290] R 1A is C 1-4 alkyl or C 3-4 cycloalkyl;

[0291] R 2A independently represents C 1-4 alkyl or C 3-4 cycloalkyl at each occurrence;

[0292] R 3A is phenyl substituted with 1, 2 or 3 substituents independently selected from halo, C1-C4 alkyl or C1-C4 haloalkyl;

[0293] R 4A is -(C 1-6 alkylene)-C(O)N(R 5A )(R 6A ), -(C 1-6 alkylene)-N(R 5A )C(O)R 7A 、-(C 1-6 alkylene)-CO2R 7A 、-(C 1-6 alkylene)-OC(O)R 7A or -(C 0-6 alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur), -(C 1-6 alkylene)-cyano, C 1-6 alkyl or hydrogen; or R 4A and R 10A together with the carbon atom to which they are attached form a C 3-5 saturated carbocyclic ring;

[0294] R5A and R 6A is independently hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl; or R 5A and R 6A together with the nitrogen atom to which they are attached form a 3- to 7-membered ring containing 1 nitrogen atom;

[0295] R 7A is C 1-6 alkyl, -(C 1-6 alkylene)-(C 3-6 cycloalkyl) or C 3-6 cycloalkyl;

[0296] R 8A independently represents C 1-4 alkyl or -N(R 9A )2 each time it appears;

[0297] R 9A independently represents hydrogen or C 1-4 alkyl each time it appears;

[0298] R 10A is hydrogen or C 1-4 alkyl; and

[0299] p and q are independently 0, 1 or 2.

[0300] In certain embodiments, EPL is each of which is substituted by one occurrence of R II-2A where R II-2A is a bond to L.

[0301] In certain embodiments, EPL is one of the following:

[0302]

[0303] R 1A is C 1-4 alkyl or C 3-4 cycloalkyl;

[0304] R 2A independently represents C 1-4 alkyl or C 3-4 cycloalkyl each time it appears;

[0305] R 3A is a phenyl group substituted by 1, 2 or 3 substituents independently selected from halo, C1-C4 alkyl or C1-C4 haloalkyl;

[0306] R 4A is -(C 1-6(Alkylene)-C(O)N(R 5A )(R 6A )、-(C 1-6 Alkylene)-N(R 5A )C(O)R 7A 、-(C 1-6 Alkylene)-CO2R 7A 、-(C 1-6 Alkylene)-OC(O)R 7A or -(C 1-6 Alkylene)-OC(O)R 7A 。

[0307] R 5A and R 6A are independently hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl; or R 5A and R 6A together with the nitrogen atom to which they are attached form a 3- to 7-membered ring containing 1 nitrogen atom;

[0308] R 7A is C 1-6 alkyl, -(C 1-6 Alkylene)-(C 3-6 cycloalkyl) or C 3-6 cycloalkyl; and

[0309] p is 0, 1 or 2

[0310] In certain embodiments, EPL is In certain embodiments, EPL is

[0311] In certain embodiments, EPL is In certain embodiments, EPL is In certain embodiments, EPL is

[0312] As generally defined above, R 1A is C 1-4 alkyl or C 3-4 cycloalkyl. In certain embodiments, R 1A is C 1-4 alkyl. In certain embodiments, it is methyl. In certain embodiments, R 1A is C 3-4 cycloalkyl. In certain embodiments, R 1A is selected from the groups depicted in the compounds of Table 1 below.

[0313] As generally defined above, R 2A independently represents C 1-4alkyl or C 3-4 cycloalkyl. In certain embodiments, R 2A is C 1-4 alkyl. In certain embodiments, R 2A is methyl. In certain embodiments, R 2A is C 3-4 cycloalkyl. In certain embodiments, R 2A is selected from the groups depicted in the compounds of Table 1 below.

[0314] As generally defined above, R 3A is phenylhalo, C1-C4 alkyl or C1-C4 haloalkyl substituted with 1, 2 or 3 substituents independently selected from. In certain embodiments, R 3A is phenyl substituted with halo. In certain embodiments, R 3A is phenyl substituted with 1 substituent selected from halo, C1-C4 alkyl or C1-C4 haloalkyl. In certain embodiments, R 3A is phenyl substituted with 2 substituents independently selected from halo, C1-C4 alkyl or C1-C4 haloalkyl. In certain embodiments, R 3A is phenyl substituted with 3 substituents independently selected from halo, C1-C4 alkyl or C1-C4 haloalkyl. In certain embodiments, R 3A is selected from the groups depicted in the compounds of Table 1 below.

[0315] As generally defined above, R 4A is -(C 1-6 alkylene)-C(O)N(R 5A )(R 6A ), -(C 1-6 alkylene)-N(R 5A )C(O)R 7A ), -(C 1-6 alkylene)-CO2R 7A ), -(C 1-6 alkylene)-OC(O)R 7A or -(C 0-6 alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur), -(C 1-6 alkylene)-cyano, C 1-6 alkyl or hydrogen; or R 4A and R 10A together with the carbon atom to which they are attached form a C 3-5 saturated carbocycle. In certain embodiments, R 4A is -(C 1-6 alkylene)-C(O)N(R 5A )(R 6A)、-(C 1-6 alkylene)-N(R 5A )C(O)R 7A 、-(C 1-6 alkylene)-CO2R 7A 、-(C 1-6 alkylene)-OC(O)R 7A or -(C 0-6 alkylene)-(5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur). In certain embodiments, R 4A is -(C 1-6 alkylene)-C(O)N(R 5A )(R 6A )、-(C 1-6 alkylene)-N(R 5A )C(O)R 7A 、-(C 1-6 alkylene)-CO2R 7A or -(C 1-6 alkylene)-OC(O)R 7A . In certain embodiments, R 4A is -(C 1-6 alkylene)-C(O)N(R 5A )(R 6A ). In certain embodiments, R 4A is -(C 1-6 alkylene)-CO2R 7A . In certain embodiments, R 4A is -(C 1-6 alkylene)-N(R 5A )C(O)R 7A . In certain embodiments, R 4A is -(C 1-6 alkylene)-OC(O)R 7A . In certain embodiments, R 4A is -(C 0-6 alkylene)-(5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur). In certain embodiments, R 4A is -(C 1-6 alkylene)-cyano. In certain embodiments, R 4A is C 1-6 alkyl. In certain embodiments, R 4A is hydrogen. In certain embodiments, R 4A and R 10A together with the carbon atom to which they are attached form a C 3-5 saturated carbocyclic ring. In certain embodiments, R 4AThe groups depicted in the compounds selected from Table 1 below.

[0316] As generally defined above, R 5A and R 6A are independently hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl; or R 5A and R 6A together with the nitrogen atom to which they are attached form a 3- to 7-membered ring containing one nitrogen atom. In certain embodiments, R 5A and R 6A are independently hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl. In certain embodiments, R 5A is hydrogen. In certain embodiments, R 5A is C 1-6 alkyl. In certain embodiments, R 5A is C 3-6 cycloalkyl. In certain embodiments, R 6A is hydrogen. In certain embodiments, R 6A is C 1-6 alkyl. In certain embodiments, R 6A is C 3-6 cycloalkyl. In certain embodiments, R 5A and R 6A together with the nitrogen atom to which they are attached form a 3- to 7-membered ring containing one nitrogen atom. In certain embodiments, R 5A and R 6A together with the nitrogen atom to which they are attached form a 3-membered ring containing one nitrogen atom. In certain embodiments, R 5A and R 6A together with the nitrogen atom to which they are attached form a 4-membered ring containing one nitrogen atom. In certain embodiments, R 5A and R 6A together with the nitrogen atom to which they are attached form a 5-membered ring containing one nitrogen atom. In certain embodiments, R 5A and R 6A together with the nitrogen atom to which they are attached form a 6-membered ring containing one nitrogen atom. In certain embodiments, R 5A and R 6A together with the nitrogen atom to which they are attached form a 7-membered ring containing one nitrogen atom. In certain embodiments, R 5A is selected from the groups depicted in the compounds selected from Table 1 below. In certain embodiments, R 6A is selected from the groups depicted in the compounds selected from Table 1 below.

[0317] As generally defined above, R 7A is C1-6 alkyl, -(C 1-6 alkylene)-(C 3-6 cycloalkyl) or C 3-6 cycloalkyl. In certain embodiments, R 7A is C 1-6 alkyl. In certain embodiments, R 7A is -(C 1-6 alkylene)-(C 3-6 cycloalkyl). In certain embodiments, R 7A is C 3-6 cycloalkyl. In certain embodiments, R 7A is selected from the groups depicted in the compounds of Table 1 below.

[0318] As generally defined above, R 8A independently represents C 1-4 alkyl or -N(R 9A )2 each time it appears. In certain embodiments, R 8A independently represents C 1-4 alkyl each time it appears. In certain embodiments, R 8A independently represents -N(R 9A )2 each time it appears. In certain embodiments, R 8A is C 1-4 alkyl. In certain embodiments, R 8A is -N(R 9A )2. In certain embodiments, R 8A is -N(H)CH3. In certain embodiments, R 8A is selected from the groups depicted in the compounds of Table 1 below.

[0319] As generally defined above, R 9A independently represents hydrogen or C 1-4 alkyl each time it appears. In certain embodiments, R 9A independently represents C 1-4 alkyl each time it appears. In certain embodiments, R 9A is hydrogen. In certain embodiments, R 9A is C 1-4 alkyl. In certain embodiments, R 9A independently represents hydrogen or methyl each time it appears. In certain embodiments, R 9A is selected from the groups depicted in the compounds of Table 1 below.

[0320] As generally defined above, R 10A is hydrogen or C 1-4 alkyl. In certain embodiments, R 10A is hydrogen. In certain embodiments, R10A is C 1-4 alkyl. In certain embodiments, R 10A is methyl. In certain embodiments, R 10A is selected from the groups depicted in the compounds of Table 1 below. In certain embodiments, p is 2. In certain embodiments, p is 1. In certain embodiments, p is 0. In certain embodiments, t is 2. In certain embodiments, p is selected from the corresponding values of the groups depicted in the compounds of Table 1 below.

[0321] In certain embodiments, q is 2. In certain embodiments, q is 1. In certain embodiments, q is 0. In certain embodiments, q is selected from the corresponding values of the groups depicted in the compounds of Table 1 below.

[0322] In certain embodiments, EPL is defined by the variable A 2 as set forth above in connection with Formula I. In certain embodiments, EPL is defined by one or more embodiments of the variable A 2 as set forth in connection with Formula I.

[0323] The compounds can be further characterized, for example, according to the identity of L. Exemplary further embodiments of L are provided in Part C below.

[0324] Part C: Exemplary Further Description of the Linker (L) Moiety of Compounds of Formula I and Formula II

[0325] The compounds of Formula I and Formula II can be further characterized, for example, according to the identity of the linker (L) moiety. A variety of linkers are known to those skilled in the art and can be used in the heterobifunctional compounds described herein. By way of example, in certain embodiments, L comprises one or more optionally substituted groups selected from amino acids, polyether chains, aliphatic groups, and any combination thereof. In certain embodiments, L consists of one or more optionally substituted groups selected from amino acids, polyether chains, aliphatic groups, and any combination thereof. In certain embodiments, L consists of one or more groups selected from amino acids, polyether chains, aliphatic groups, and any combination thereof.

[0326] In some embodiments, L is symmetric. In some embodiments, L is asymmetric. In certain embodiments, L is a bond.

[0327] In certain embodiments, L is a covalent bond or a divalent C 1-30 saturated or unsaturated, straight-chain or branched-chain hydrocarbon chain, wherein 1-15 methylene units of L are optionally and independently replaced by: cyclopropylidene, -N(H)-, -N(C 1-4 alkyl)-, -N(C 3-5cycloalkyl)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, -S(O)2N(H)-, -S(O)2N(C 1-4 alkyl)-, -S(O)2N(C 3-5 cycloalkyl)-, -N(H)C(O)-, -N(C 1-4 alkyl)C(O)-, -N(C 3-5 cycloalkyl)C(O)-, -C(O)N(H)-, -C(O)N(C 1-4 alkyl)-, -C(O)N(C 3-5 cycloalkyl)-, phenylene, 8-10 membered bicyclic arylene, 4-7 membered saturated or partially unsaturated carbocyclic group, 8-10 membered bicyclic saturated or partially unsaturated carbocyclic group, 3-7 membered saturated or partially unsaturated heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, 8-10 membered bicyclic saturated or partially unsaturated heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 8-10 membered bicyclic heteroarylene having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0328] In certain embodiments, L is a divalent, saturated or unsaturated, straight or branched chain C 1-60 hydrocarbon chain, wherein 0-20 methylene units of said hydrocarbon are independently replaced by: -O-, -S-, -N(R**)-, -OC(O)-, -C(O)O-, -S(O)-, -S(O)2-, -N(R**)S(O)2-, -S(O)2N(R**)-, -N(R**)C(O)-, -C(O)N(R**)-, -OC(O)N(R**)-, -N(R**)C(O)O-, optionally substituted 3-10 membered carbocyclic group, or optionally substituted 3-10 membered heterocyclic group having 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein R** independently represents hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl.

[0329] In certain embodiments, L is a divalent, saturated or unsaturated, straight or branched chain C 1-60 hydrocarbon chain, wherein 0-20 methylene units of said hydrocarbon are independently replaced by: -O-, -S-, -N(H)-, -N(C 1-6 alkyl)-, -OC(O)-, -C(O)O-, -S(O)-, -S(O)2-, -N(H)S(O)2-, -N(C 1-6 alkyl)S(O)2-, -S(O)2N(H)-, -S(O)2N(C1-6 alkyl)-, -N(H)C(O)-, -N(C 1-6 alkyl)C(O)-, -C(O)N(H)-, -C(O)N(C 1-6 alkyl)-, -OC(O)N(H)-, -OC(O)N(C 1-6 alkyl)-, -N(H)C(O)O-, -N(C 1-6 alkyl)C(O)O-, an optionally substituted 3- to 10-membered carbocyclic group, or an optionally substituted 3- to 10-membered heterocyclic group containing 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0330] In certain embodiments, L is a divalent, saturated, straight or branched chain C 3-30 hydrocarbon chain, wherein 0 to 15 methylene units of said hydrocarbon are independently replaced by: -O-, -N(H)-, -N(C 1-6 alkyl)-, -OC(O)-, -C(O)O-, -N(H)C(O)-, -N(C 1-6 alkyl)C(O)-, -C(O)N(H)-, -C(O)N(C 1-6 alkyl)-, a 3- to 10-membered carbocyclic group, or a 3- to 10-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0331] In certain embodiments, L is a divalent, saturated, straight or branched chain C 3-30 hydrocarbon chain, wherein 0 to 15 methylene units of said hydrocarbon are independently replaced by: -O-, -N(H)-, -N(C 1-6 alkyl)-, -OC(O)-, -C(O)O-, -N(H)C(O)-, -N(C 1-6 alkyl)C(O)-, -C(O)N(H)- or -C(O)N(C 1-6 alkyl)-.

[0332] In other embodiments, L comprises a polyethylene glycol chain having a size in the range of from about 1 to about 12 ethylene glycol units, from about 1 to about 10 ethylene glycol units, from about 2 to about 6 ethylene glycol units, from about 2 to about 5 ethylene glycol units or from about 2 to about 4 ethylene glycol units. In other embodiments, L is a polyethylene glycol chain bivalent group having a size in the range of from about 1 to about 12 ethylene glycol units, from about 1 to about 10 ethylene glycol units, from about 2 to about 6 ethylene glycol units, from about 2 to about 5 ethylene glycol units or from about 2 to about 4 ethylene glycol units.

[0333] In certain embodiments, L is a heteroalkylene having from 4 to 30 atoms selected from carbon, oxygen, nitrogen, and sulfur. In certain embodiments, L is a heteroalkylene having from 4 to 20 atoms selected from carbon, oxygen, nitrogen, and sulfur. In certain embodiments, L is a heteroalkylene having from 4 to 10 atoms selected from carbon, oxygen, nitrogen, and sulfur. In certain embodiments, L is a heteroalkylene having from 4 to 30 atoms selected from carbon, oxygen, and nitrogen. In certain embodiments, L is a heteroalkylene having from 4 to 20 atoms selected from carbon, oxygen, and nitrogen. In certain embodiments, L is a heteroalkylene having from 4 to 10 atoms selected from carbon, oxygen, and nitrogen. In certain embodiments, L is a heteroalkylene having from 4 to 30 atoms selected from carbon and oxygen. In certain embodiments, L is a heteroalkylene having from 4 to 20 atoms selected from carbon and oxygen. In certain embodiments, L is a heteroalkylene having from 4 to 10 atoms selected from carbon and oxygen.

[0334] In additional embodiments, L is an optionally substituted (poly)ethylene glycol having from 1 to about 100 ethylene glycol units, from about 1 to about 50 ethylene glycol units, 1 to about 25 ethylene glycol units, from about 1 to about 10 ethylene glycol units, 1 to about 8 ethylene glycol units, 1 to about 6 ethylene glycol units, 2 to about 4 ethylene glycol units, or an optionally substituted alkyl group interspersed with optionally substituted O, N, S, P, or Si atoms. In certain embodiments, L is substituted with an aryl, phenyl, benzyl, alkyl, alkylene, or heterocyclic group.

[0335] In certain embodiments, L is a divalent, saturated or unsaturated, straight-chain or branched-chain C 1-45 hydrocarbon chain, wherein 0-10 methylene units of the hydrocarbon are independently replaced with: -O-, -S-, -N(R*)-, -OC(O)-, -C(O)O-, -S(O)-, -S(O)2-, -N(R*)S(O)2-, -S(O)2N(R*)-, -N(R*)C(O)-, -C(O)N(R*)-, -OC(O)N(R*)-, -N(R*)C(O)O-, an optionally substituted carbocyclic group, or an optionally substituted heterocyclic group, wherein R* independently represents hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl.

[0336] In certain embodiments, L is a divalent, saturated or unsaturated, straight-chain or branched-chain C 1-45a hydrocarbon chain, wherein 0-10 methylene units of the hydrocarbon are independently replaced by: -O-, -S-, -N(R*)-, -OC(O)-, -C(O)O-, -S(O)-, -S(O)2-, -N(R*)S(O)2-, -S(O)2N(R*)-, -N(R*)C(O)-, -C(O)N(R*)-, -OC(O)N(R*)-, -N(R*)C(O)O-, an optionally substituted 3-10 membered carbocyclic group, or an optionally substituted 3-10 membered heterocyclic group containing 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen and sulfur, wherein R* independently represents hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl.

[0337] In certain embodiments, L has the formula -N(R)-(optionally substituted 3-20 membered heteroalkylene) p -CH2-C(O)-, wherein R is hydrogen or an optionally substituted C1-C6 alkyl, and p is 0 or 1.

[0338] In certain embodiments, L has the formula -N(R)-(3-20 membered heteroalkylene) p -CH2-C(O)-; wherein the 3-20 membered heteroalkylene is optionally substituted with 1, 2, 3 or 4 substituents independently selected from halogen, C1-C6 haloalkyl, C3-C6 cycloalkyl, hydroxy and cyano; R is hydrogen or an optionally substituted C1-C6 alkyl; and p is 0 or 1.

[0339] In certain embodiments, L has the formula -N(R)-(3-20 membered heteroalkylene) p -CH2-C(O)-; wherein the 3-20 membered heteroalkylene is optionally substituted with 1, 2 or 3 substituents independently selected from halogen and C1-C6 haloalkyl; R is hydrogen or C1-C6 alkyl; and p is 0 or 1.

[0340] In certain embodiments, L is a divalent, saturated or unsaturated, straight or branched chain C 1-60 hydrocarbon chain, wherein 0-20 methylene units of the hydrocarbon are independently replaced by: -O-, -S-, -N(H)-, -N(C 1-6 alkyl)-, -OC(O)-, -C(O)O-, -S(O)-, -S(O)2-, -N(H)S(O)2-, -N(C 1-6 alkyl)S(O)2-, -S(O)2N(H)-, -S(O)2N(C 1-6 alkyl)-, -N(H)C(O)-, -N(C 1-6 alkyl)C(O)-, -C(O)N(H)-, -C(O)N(C1-6 -alkyl)-, -OC(O)N(H)-, -OC(O)N(C 1-6 -alkyl)-, -N(H)C(O)O-, -N(C 1-6 -alkyl)C(O)O-, an optionally substituted 3- to 10-membered carbocyclic group, or an optionally substituted 3- to 10-membered heterocyclic group containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0341] In certain embodiments, L is a divalent, saturated, straight-chain or branched-chain C 3-30 hydrocarbon chain, wherein 0 to 15 methylene units of the hydrocarbon are independently replaced by: -O-, -N(H)-, -N(C 1-6 -alkyl)-, -OC(O)-, -C(O)O-, -N(H)C(O)-, -N(C 1-6 -alkyl)C(O)-, -C(O)N(H)-, -C(O)N(C 1-6 -alkyl)-, a 3- to 10-membered carbocyclic group, or a 3- to 10-membered heterocyclic group containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0342] In certain embodiments, L is a divalent, saturated, straight-chain or branched-chain C 3-30 hydrocarbon chain, wherein 0 to 15 methylene units of the hydrocarbon are independently replaced by: -O-, -N(H)-, -N(C 1-6 -alkyl)-, -OC(O)-, -C(O)O-, -N(H)C(O)-, -N(C 1-6 -alkyl)C(O)-, -C(O)N(H)-, or -C(O)N(C 1-6 -alkyl)-.

[0343] In certain embodiments, L is a divalent, saturated or unsaturated, straight-chain or branched-chain C 5-40 hydrocarbon chain, wherein 1 to 20 methylene units of the hydrocarbon are independently replaced by: -O-, -N(H)-, -N(C 1-6 -alkyl)-, -N(H)C(O)-, -N(C 1-6 -alkyl)C(O)-, -C(O)N(H)-, -C(O)N(C 1-6 -alkyl)-, an optionally substituted 3- to 10-membered carbocyclic group, or an optionally substituted 3- to 10-membered heterocyclic group containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0344] In certain embodiments, L is -(a 3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(OCH2CH2) 1-15 -O-***, wherein *** is attached to A 2The connecting point.

[0345] In certain embodiments, L is -(a 3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(OCH2CH2) 1-5 -O-***, where *** is the connecting point to A 2 The connecting point.

[0346] In certain embodiments, L is -(a 3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(OCH2CH2) 6-10 -O-***, where *** is the connecting point to A 2 The connecting point.

[0347] In certain embodiments, L is -piperidinyl-(OCH2CH2) 1-15 -O-***, where *** is the connecting point to A 2 The connecting point.

[0348] In certain embodiments, L is where *** is the connecting point to A 2 The connecting point. In certain embodiments, L is where *** is the connecting point to A 2 The connecting point. In certain embodiments, L is where *** is the connecting point to A 2 The connecting point.

[0349] In certain embodiments, L is -(a 3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(OCH2CH2) 1-15 -N(H)C(O)-C 1-10 alkylene-***, -(a 3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(OCH2CH2) 1-15 -N(C 1-4 alkyl)C(O)-C 1-10 alkylene-***, -(a 3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(OCH2CH2) 1-15 -C(O)N(H)-C 1-10 alkylene-*** or -(a 3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(OCH2CH2) 1-15 -C(O)N(C 1-4 alkyl)-C 1-10 alkylene-***, where *** is the connecting point to A 2 The connecting point.

[0350] In certain embodiments, L is -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(OCH2CH2) 1-10 -N(H)C(O)-C 1-5 alkylene-***, -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(OCH2CH2) 1-10 -N(C 1-4 alkyl)C(O)-C 1-5 alkylene-***, -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(OCH2CH2) 1-10 -C(O)N(H)-C 1-5 alkylene-*** or -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-OCH2CH2) 1-10 -C(O)N(C 1-4 alkyl)-C 1-5 alkylene-***, where *** is the point of attachment to A 2 of.

[0351] In certain embodiments, L is -piperidinyl-(OCH2CH2) 1-5 -N(H)C(O)-C 1-5 alkylene-***, -piperidinyl-(OCH2CH2) 1-5 -N(C 1-4 alkyl)C(O)-C 1-5 alkylene-***, -piperidinyl-(OCH2CH2) 1-5 -C(O)N(H)-C 1-5 alkylene-*** or -piperidinyl-(OCH2CH2) 1-5 -C(O)N(C 1-4 alkyl)-C 1-5 alkylene-***, where *** is the point of attachment to A 2 of.

[0352] In certain embodiments, L is -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(OCH2CH2) 1-10 -***, -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-10 alkylene)-O-*** or -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-C 1-10 alkylene, where *** is the point of attachment to A 2 of.

[0353] In certain embodiments, L is -piperidinyl-(OCH2CH2)1-5 -***, -piperidinyl-(C 0-5 alkylene)-O-*** or -piperidinyl-(C 1-5 alkylene)-***, where *** is the point of attachment to A 2 .

[0354] In certain embodiments, L is -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-X 1 -***, where *** is the point of attachment to A 2 and X 1 is (i) C 1-10 alkylene, where 1 or 2 methylenes are optionally replaced by -O-, -N(H)- or -N(C 1-4 alkyl)-, (ii) a 3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen, or (iii) -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(C 1-10 alkylene)-.

[0355] In certain embodiments, L is -(piperidinyl)-X 1 -***, where *** is the point of attachment to A 2 and X 1 is (i) C 1-5 alkylene, where 1 or 2 methylenes are optionally replaced by -O-, -N(H)- or -N(C 1-4 alkyl)-, (ii) a 3- to 4-membered monocyclic saturated heterocycle containing 1 heteroatom selected from nitrogen, or (iii) -(3- to 4-membered monocyclic saturated heterocycle containing 1 heteroatom selected from nitrogen)-(C 1-5 alkylene)-.

[0356] In certain embodiments, L is where *** is the point of attachment to A 2 and X 1 is (i) C 1-10 alkylene, where 1 or 2 methylenes are optionally replaced by -O-, -N(H)- or -N(C 1-4 alkyl)-, (ii) a 3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen, or (iii) -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(C 1-10 alkylene)-.

[0357] In certain embodiments, L is -(piperazinyl)-X 1 -***, where *** is the point of attachment to A 2 and X 1 is (i) C1-5 an alkylene group in which one or two methylene groups are optionally replaced by -O-, (ii) a 3- to 4-membered monocyclic saturated heterocycle containing one heteroatom selected from nitrogen, or (iii) -(a 3- to 4-membered monocyclic saturated heterocycle containing one heteroatom selected from nitrogen)-(C 1-5 alkylene)-.

[0358] In certain embodiments, L is where *** is the point of attachment to A 2 and X 1 is (i) C 1-10 an alkylene group in which one or two methylene groups are optionally replaced by -O-, (ii) a 3- to 7-membered monocyclic saturated heterocycle containing one or two heteroatoms selected from nitrogen, or (iii) -(a 3- to 7-membered monocyclic saturated heterocycle containing one or two heteroatoms selected from nitrogen)-(C 1-10 alkylene)-.

[0359] In certain embodiments, L is -(a 3- to 7-membered monocyclic saturated heterocycle containing one or two heteroatoms selected from nitrogen)-X 2 -(C 1-10 alkylene)-***, where *** is the point of attachment to A 2 and X 2 is -O-, -N(H)- or -N(C 1-6 alkyl)-. In certain embodiments, L is -(a 3- to 7-membered monocyclic saturated heterocycle containing one or two heteroatoms selected from nitrogen)-X 2 -(C 1-10 alkylene)-***, where *** is the point of attachment to A 2 and X 2 is -O-.

[0360] In certain embodiments, L is -(piperidinyl)-X 2 -(C 1-10 alkylene)-***, where *** is the point of attachment to A 2 and X 2 is -O-, -N(H)- or -N(C 1-6 alkyl)-. In certain embodiments, L is -(piperidinyl)-X 2 -(C 1-10 alkylene)-***, where *** is the point of attachment to A 2 and X 2 is -O-.

[0361] In certain embodiments, L is -(piperidinyl)-X 2 -(a 3- to 7-membered monocyclic saturated heterocycle containing one or two heteroatoms selected from nitrogen)-***, where *** is the point of attachment to A2 a linking point, and X 2 is -O-, -N(H)- or -N(C 1-6 alkyl)-. In certain embodiments, L is -(piperidinyl)-X 2 -(a 3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-***, wherein *** is the linking point to A 2 and X 2 is -O-.

[0362] In certain embodiments, L is wherein *** is the linking point to A 2 and X 2 is -O-, -N(H)- or -N(C 1-6 alkyl)-. In certain embodiments, L is wherein *** is the linking point to A 2 and X 2 is -O-.

[0363] In certain embodiments, L is wherein *** is the linking point to A 2 and X 2 is -O-, -N(H)- or -N(C 1-6 alkyl)-. In certain embodiments, L is wherein *** is the linking point to A 2 and X 2 is -O-.

[0364] In certain embodiments, L is -(a 3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-X 1 -***, wherein *** is the linking point to A 2 and X 1 is -(OCH2CH2) 1-10 wherein 1 CH2 group is optionally replaced by -C(H)(C 3-6 cycloalkyl)-.

[0365] In certain embodiments, L is a 7- to 11-membered spiro or fused bicyclic saturated heterocycle containing 1, 2 or 3 heteroatoms selected from nitrogen and oxygen. In certain embodiments, L is a 7- to 8-membered spiro or fused bicyclic saturated heterocycle containing 2 heteroatoms selected from nitrogen.

[0366] In certain embodiments, L is -(a 3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-X 3 -(a 3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-, wherein X 3 is C1-10 alkylene, -O-, -N(H)-, -N(C 1-4 alkyl)- or a bond.

[0367] In certain embodiments, L is -(piperidinylene)-(C 1-5 alkylene)-(piperazinylene)-***, where *** is the point of attachment to A 2

[0368] In certain embodiments, L is -(piperazinylene)-(azetidinylene)-*** or (azetidinylene)-(piperazinylene)-***, where *** is the point of attachment to A 2

[0369] In certain embodiments, L is -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-X 3 -(C 3-6 subcycloalkylene)-O-***, -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-X 3 -(C 3-6 subcycloalkylene)-N(H)-*** or -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-X 3 -(C 3-6 subcycloalkylene)-N(C 1-4 alkyl)-***, where *** is the point of attachment to A 2 and X 3 is C 1-10 alkylene, -O-, -N(H)-, -N(C 1-4 alkyl)- or a bond.

[0370] In certain embodiments, L is -(piperidinylene)-X 3 -(C 3-6 subcycloalkylene)-O-***, -(piperidinylene)-X 3 -(C 3-6 subcycloalkylene)-N(H)-*** or -(piperidinylene)-X 3 -(C 3-6 subcycloalkylene)-***, where *** is the point of attachment to A 2 and X 3 is C 1-10 alkylene, -O-, -N(H)-, -N(C 1-4 alkyl)- or a bond.

[0371] In certain embodiments, L has the formula -(C 0-12 alkylene)-(optionally substituted 3- to 40-membered heteroalkylene)-(C 0-12 ​​-alkylene)-

[0372] In certain embodiments, L is where *** is the point of attachment to A 2 of the bond.

[0373] In certain embodiments, L is where *** is the point of attachment to A 2 of the bond.

[0374] In certain embodiments, L is where *** is the point of attachment to A 2 of the bond.

[0375] In certain embodiments, L is where *** is the point of attachment to A 2 of the bond.

[0376] In certain embodiments, L is -(8-12-membered spiroheterocyclic group containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-(C 3-4 subcycloalkyl)-***, -(8-12-membered spiroheterocyclic group containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-(C 0-4 alkylene)-***, -(8-12-membered spiroheterocyclic group containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-C(O)-(C 1-4 alkylene)-***, -(5-6-membered saturated monocyclic heterocyclic group containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-(3-5-membered saturated monocyclic heterocyclic group containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-***, -(5-6-membered saturated monocyclic heterocyclic group containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-O-***, -(5-6-membered saturated monocyclic heterocyclic group containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-(C 0-4 alkylene)-***, -(5-6-membered saturated monocyclic heterocyclic group containing 1 or 2 heteroatoms)-(C 0-4 alkylene)-O-***, -(8-12-membered spiroheterocyclic group containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-C(O))-***, -(8-12-membered spiroheterocyclic group containing 1 or 2 heteroatoms selected from nitrogen)-O-(C 0-6 alkylene)-***, -(8-12-membered spiroheterocyclic group containing 1 or 2 heteroatoms selected from nitrogen)-(C 1-6 alkylene)-O-(C 0-6-alkylene)-***, -(5- or 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms)-C(O)N(H)-(C 0-6 -alkylene)-***, -(N(C 1-6 -alkyl)-(C 0-6 -alkylene)-C(O)N(H)-(C 0-6 -alkylene)-***, -(8- to 12-membered spiro heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-(C 2-4 -alkynylene)-***, -(5- or 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-(C 1-6 -alkyl)-(5- or 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-***, -(5- or 6-membered saturated monocyclic heterocyclylene containing 1 or 2 nitrogen heteroatoms)-C(O)N(H)-(C 0-6 -alkylene)-N(H))-***, -(C(O)N(H)-(C 0-6 -alkylene)-(5- or 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms)-***, -(5- or 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-N(C 1-6 -alkyl)-(5- or 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-O-***, -C(O)-(5- or 6-membered saturated monocyclic heterocyclylene containing 1 or 2 nitrogen heteroatoms)-C(O)-***, -(C 0-6 -alkylene)-(5- or 6-membered saturated monocyclic heterocyclylene containing 1 or 2 nitrogen heteroatoms)-C(O)-***, -(5- or 6-membered saturated monocyclic heterocyclylene containing 1 or 2 nitrogen heteroatoms)-C(O)-(C 0-6 -alkylene)***, -C(O)-(5- or 6-membered saturated monocyclic heterocyclylene containing 1 or 2 nitrogen heteroatoms)-(C 1-6 -alkylene)-***, -(C(O)N(H)-(C 1-6 -alkylene)-C(O)N(H)-(C 0-6 -alkylene)-*** or -(8- to 11-membered fused bicyclic heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-(C 1-4 -alkylene)-***, wherein *** is the point of attachment to A 2 of.

[0377] In certain embodiments, L is -N(C 1-6 -alkyl)-(5- or 6-membered saturated monocyclic heterocyclylene containing 1 or 2 nitrogen heteroatoms)-C(O)-(C 0-6-(alkylene)-***, -(5- or 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-(5- or 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-4 -(alkylene)-O-***, -(C 0-6 -(alkylene)-N(H)C(O)N(H)-(C 0-6 -(alkylene)-***, -N(H)-(C 0-6 -(alkylene)-(5- or 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-6 -(alkylene)-***, -(C 0-6 -(alkylene)-C(O)-(5- or 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-6 -(alkylene)-***, -(C 0-6 -(alkylene)-(5- or 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-C(O)N(C 1-6 -alkyl)-(C 0-6 -(alkylene)-***, -(C 0-6 -(alkylene)-(5- or 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-6 -(alkylene)-N(C 1-6 -alkyl)-(3- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-***, -(4- to 6-membered monocyclic heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-6 -(alkylene)-O-(5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen)-O-***, -(4- to 6-membered monocyclic heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-6 -(alkylene)-(5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen)-O-***, -(4- to 6-membered monocyclic heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-6 -(alkylene)-(5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen)-***, -(8- to 12-membered spiro heterocyclic group substituted with 1 or 2 fluorines and containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-(C 1-4 -(alkylene)-***, -(5- or 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-4 -(alkylene)-(C 3-6 -(subcycloalkyl)-(C 0-4 -(alkylene)-O-***, -(5- or 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-4 -(alkylene)-(C 3-6 -(subcycloalkyl)-(C0-4 alkylene)-***, -(C 0-4 alkylene)-(8-12-membered spiroheterocyclic group containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-***, -(C 0-4 alkylene)-(C 3-6 subcycloalkyl)-(C 2-4 alkynylene)-***, -(C 0-4 alkylene)-(8-10-membered fused bicyclic heterocyclic group substituted with 1 or 2 fluorines and containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-4 alkylene)-***, -(8-12-membered spiroheterocyclic group containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-O-***, -(8-12-membered spiroheterocyclic group containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-(C 0-4 alkylene)-(5-6-membered saturated monocyclic heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen)-***, -(C 0-4 alkylene)-(4-6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen)-(phenyl group substituted with trifluoromethyl)-(C 0-4 alkylene)-N(H)-***, or -(5-6-membered saturated monocyclic heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen)-C(O)-(5-6-membered saturated monocyclic heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-6 alkylene)-***, -(C 3-6 subcycloalkyl)-C(O)N(C 1-6 alkyl)(C 0-6 alkylene)-***, -(5-6-membered saturated monocyclic heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen)-(phenyl group substituted with 0 or 1 occurrence of methyl or halogen)-(C 0-6 alkylene)-***, -(5-6-membered saturated monocyclic heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-6 alkylene)-(5-6-membered saturated monocyclic heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen and substituted with oxo group)-(C 0-6 alkylene)-***, -(8-12-membered spiroheterocyclic group containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen and substituted with C 1-4 alkyl)-heterocyclic group)-(C 0-6 alkylene)-(O) 0-1 ***, -(C 2-4 alkynylene)-(8-12-membered spiroheterocyclic group containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-(C 0-4 alkylene)-***, -(C 0-4 alkylene)-(C 3-7Subcycloalkyl)-(C 2-4 Subalkynyl)-***, -(C 1-4 Subalkyl)-(8-12-membered spiroheterocyclic group containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-(C 0-4 Subalkyl)-***, -(C 1-4 Subalkyl)-(5-7-membered saturated heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-(C 0-4 Subalkyl)-***, -(C 0-4 Subalkyl)-(5-7-membered saturated heterocyclic group containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-(C 2-4 Subenyl)-*** or -(C 0-4 Subalkyl)-(6-8-membered saturated heterocyclic group substituted with 1 or 2 fluorines and containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-(C 0-4 Subalkyl)-***, wherein *** is the point of attachment to A 2 The point of attachment.

[0378] Additional Exemplary Embodiments of L

[0379] In certain embodiments, L is -N(H)-(C 2-9 Subalkyl)-O-(C 1-6 Subalkyl)-C(O)-***, -N(H)-(C 10-20 Subalkyl)-O-(C 1-6 Subalkyl)-C(O)-***, -N(H)-[(C 2-4 Subalkyl)-O-] 2-6 -(C 1-6 Subalkyl)-C(O)-***, -N(H)-[(C 2-4 Subalkyl)-O-] 7-15 -(C 1-6 Subalkyl)-C(O)-***, -N(H)-(C 1-6 Subalkyl)-C(O)-***, -N(H)-(C 7-15 Subalkyl)-C(O)-***, -N(H)-[(C 2-4 Subalkyl)-O-] 2-6 -(C 1-6 Subalkyl)-***, -N(H)-[(C 2-4 Subalkyl)-O-] 7-15 -(C 1-6 Subalkyl)-***, -N(H)-(C 2-9 Subalkyl)-O-(C 1-6 Subalkyl)-C(O)N(C 1-6 Alkyl)-(C 1-6-alkylene)-***, -N(H)-(C 2-9 -alkylene)-O-(C 1-6 -alkylene)-C(O)N(H)-(C 1-6 -alkylene)-***, -N(H)-[(C 2-4 -alkylene)-O-] 2-6 -(C 1-6 -alkylene)-N(H)-(C 1-6 -alkylene)-***, -N(H)-[(C 2-4 -alkylene)-O-] 7-15 -(C 1-6 -alkylene)-N(H)-(C 1-6 -alkylene)-***, -N(H)-[(C 2-4 -alkylene)-O-] 2-6 -(C 1-6 -alkylene)-N(C 1-6 -alkyl)-(C 1-6 -alkylene)-*** or -N(H)-[(C 2-4 -alkylene)-O-] 7-15 -(C 1-6 -alkylene)-N(C 1-6 -alkyl)-(C 1-6 -alkylene)-***, where *** is the point of attachment to A 2 of.

[0380] In certain embodiments, L is -N(H)-(C 2-9 -alkylene)-O-(C 1-6 -alkylene)-C(O)-***, -N(H)-(C 10-20 -alkylene)-O-(C 1-6 -alkylene)-C(O)-***, -N(H)-[CH2CH2-O-] 2-6 -(C 1-6 -alkylene)-C(O)-***, -N(H)-[CH2CH2-O-] 7-15 -(C 1-6 -alkylene)-C(O)-***, -N(H)-(C 1-6 -alkylene)-C(O)-***, -N(H)-(C 7-15 -alkylene)-C(O)-***, -N(H)-[CH2CH2-O-] 2-6 -(C 1-6 -alkylene)-***, -N(H)-[CH2CH2-O-] 7-15 -(C 1-6 -alkylene)-***, -N(H)-(C 2-9 -alkylene)-O-(C1-6 (Alkylene)-C(O)N(C 1-6 alkyl)-(C 1-6 alkylene)-***, -N(H)-(C 2-9 alkylene)-O-(C 1-6 alkylene)-C(O)N(H)-(C 1-6 alkylene)-***, -N(H)-[CH2CH2-O-] 2-6 -(C 1-6 alkylene)-N(H)-(C 1-6 alkylene)-***, -N(H)-[CH2CH2-O-] 7-15 -(C 1-6 alkylene)-N(H)-(C 1-6 alkylene)-***, -N(H)-[CH2CH2-O-] 2-6 -(C 1-6 alkylene)-N(C 1-6 alkyl)-(C 1-6 alkylene)-*** or -N(H)-[CH2CH2-O-] 7-15 -(C 1-6 alkylene)-N(C 1-6 alkyl)-(C 1-6 alkylene)-***, where *** is the point of attachment to A 2 of.

[0381] In certain embodiments, L is -N(H)-[(C 2-4 alkylene)-O-] 2-6 -(C 1-6 alkylene)-C(O)-***, -N(H)-[(C 2-4 alkylene)-O-] 7-15 -(C 1-6 alkylene)-C(O)-***, -N(H)-(C 1-6 alkylene)-N(C 1-6 alkyl)C(O)-(C 1-6 alkylene)***, -N(H)-(C 1-6 alkylene)-N(H)C(O)-(C 1-6 alkylene)***, -N(H)-(C 2-6 alkylene)-***, -N(H)-(C 7-15 alkylene)-***, -N(C 1-6 alkyl)-(C 2-6 alkylene)-***, -N(C 1-6 alkyl)-(C 7-15 alkylene)-***, -N(H)-[(C2-4 -(alkylene)-O-] 2-6 -(C 1-6 alkylene)-***, -N(H)-[(C 2-4 alkylene)-O-] 7-15 -(C 1-6 alkylene)-***, -N(H)-(C 1-6 alkylene)-(3-6 membered heteroalkyl)-(C 1-6 alkylene)-N(C 1-6 alkyl)-(C 1-6 alkylene)-***, -N(H)-(C 1-6 alkylene)-(3-6 membered heteroalkyl)-(C 1-6 alkylene)-N(H)-(C 1-6 alkylene)-***, -N(H)-(C 2-6 alkylene)-N(H)-(C 1-6 alkylene)-*** or -N(H)-(C 2-6 alkylene)-N(C 1-6 alkyl)-(C 1-6 alkylene)-***, where *** is the point of attachment to A 2 of

[0382] In certain embodiments, L is -N(H)-[CH2CH2-O-] 2-6 -(C 1-6 alkylene)-C(O)-***, -N(H)-[CH2CH2-O-] 7-15 -(C 1-6 alkylene)-C(O)-***, -N(H)-(C 1-6 alkylene)-N(C 1-6 alkyl)C(O)-(C 1-6 alkylene)***, -N(H)-(C 1-6 alkylene)-N(H)C(O)-(C 1-6 alkylene)***, -N(H)-(C 2-6 alkylene)-***, -N(H)-(C 7-15 alkylene)-***, -N(C 1-6 alkyl)-(C 2-6 alkylene)-***, -N(C 1-6 alkyl)-(C 7-15 alkylene)-***, -N(H)-[CH2CH2-O-] 2-6 -(C 1-6 alkylene)-***, -N(H)-[CH2CH2-O-] 7-15 -(C1-6 alkylene)-***, -N(H)-(C 1-6 alkylene)-(3- to 6-membered heteroalkylene)-(C 1-6 alkylene)-N(C 1-6 alkyl)-(C 1-6 alkylene)-***, -N(H)-(C 1-6 alkylene)-(3- to 6-membered heteroalkylene)-(C 1-6 alkylene)-N(H)-(C 1-6 alkylene)-***, -N(H)-(C 2-6 alkylene)-N(H)-(C 1-6 alkylene)-*** or -N(H)-(C 2-6 alkylene)-N(C 1-6 alkyl)-(C 1-6 alkylene)-***, where *** is the point of attachment to A 2 the point of attachment.

[0383] In certain embodiments, L is -[(C 2-4 alkylene)-O-] 2-6 -(C 1-6 alkylene)-***, -[(C 2-4 alkylene)-O-] 7-15 -(C 1-6 alkylene)-***, -[(C 2-4 alkylene)-O-] 2-6 -(C 1-6 alkylene)-N(C 1-6 alkyl)(C 1-6 alkylene)-***, -[(C 2-4 alkylene)-O-] 7-15 -(C 1-6 alkylene)-N(C 1-6 alkyl)(C 1-6 alkylene)-***, -[(C 2-4 alkylene)-O-] 2-6 -(C 1-6 alkylene)-N(H)(C 1-6 alkylene)-***, -[(C 2-4 alkylene)-O-] 7-15 -(C 1-6 alkylene)-N(H)(C 1-6 alkylene)-***, -(C 1-9 alkylene)-C(O)N(H)-(C 1-6 alkylene)-***, -(C 1-9 alkylene)-N(H)C(O)-(C 1-6-Alkylene)-***, -(C 1-9 -Alkylene)-C(O)N(H)-[(C 2-4 -Alkylene)-O-] 2-6 -(C 1-6 -Alkylene)-***, -(C 1-9 -Alkylene)-N(H)C(O)-[(C 2-4 -Alkylene)-O-] 2-6 -(C 1-6 -Alkylene)-***, -(C 1-9 -Alkylene)-C(O)N(H)-[(C 2-4 -Alkylene)-O-] 7-15 -(C 1-6 -Alkylene)-***, -(C 1-9 -Alkylene)-N(H)C(O)-[(C 2-4 -Alkylene)-O-] 7-15 -(C 1-6 -Alkylene)-***, -(C 1-9 -Alkylene)-C(O)N(H)-[(C 2-4 -Alkylene)-O-] 2-6 -(C 1-6 -Alkylene)-N(C 1-6 -Alkyl)-(C 1-6 -Alkylene)-***, -(C 1-9 -Alkylene)-N(H)C(O)-[(C 2-4 -Alkylene)-O-] 2-6 -(C 1-6 -Alkylene)-N(C 1-6 -Alkyl)-(C 1-6 -Alkylene)-***, -(C 1-9 -Alkylene)-C(O)N(H)-[(C 2-4 -Alkylene)-O-] 7-15 -(C 1-6 -Alkylene)-N(C 1-6 -Alkyl)-(C 1-6 -Alkylene)-*** or -(C 1-9 -Alkylene)-N(H)C(O)-[(C 2-4 -Alkylene)-O-] 7-15 -(C 1-6 -Alkylene)-N(C 1-6 -Alkyl)-(C 1-6 -Alkylene)-***, where *** is the point of attachment to A 2 of

[0384] In certain embodiments, L is -[CH2CH2-O-] 2-6 -(C1-6 -(alkylene)-***, -[CH2CH2-O-] 7-15 -(C 1-6 -(alkylene)-***, -[CH2CH2-O-] 2-6 -(C 1-6 -(alkylene)-N(C 1-6 alkyl)(C 1-6 -(alkylene)-***, -[CH2CH2-O-] 7-15 -(C 1-6 -(alkylene)-N(C 1-6 alkyl)(C 1-6 -(alkylene)-***, -[CH2CH2-O-] 2-6 -(C 1-6 -(alkylene)-N(H)(C 1-6 -(alkylene)-***, -[CH2CH2-O-] 7-15 -(C 1-6 -(alkylene)-N(H)(C 1-6 -(alkylene)-***, -(C 1-9 -(alkylene)-C(O)N(H)-(C 1-6 -(alkylene)-***, -(C 1-9 -(alkylene)-N(H)C(O)-(C 1-6 -(alkylene)-***, -(C 1-9 -(alkylene)-C(O)N(H)-[CH2CH2-O-] 2-6 -(C 1-6 -(alkylene)-***, -(C 1-9 -(alkylene)-N(H)C(O)-[CH2CH2-O-] 2-6 -(C 1-6 -(alkylene)-***, -(C 1-9 -(alkylene)-C(O)N(H)-[CH2CH2-O-] 7-15 -(C 1-6 -(alkylene)-***, -(C 1-9 -(alkylene)-N(H)C(O)-[CH2CH2-O-] 7-15 -(C 1-6 -(alkylene)-***, -(C 1-9 -(alkylene)-C(O)N(H)-[CH2CH2-O-] 2-6 -(C 1-6 -(alkylene)-N(C 1-6 alkyl)-(C 1-6 -(alkylene)-***, -(C 1-9 -(alkylene)-N(H)C(O)-[CH2CH2-O-] 2-6 -(C1-6 Alkylene)-N(C 1-6 Alkyl)-(C 1-6 Alkylene)-***, -(C 1-9 Alkylene)-C(O)N(H)-[CH2CH2-O-] 7-15 -(C 1-6 Alkylene)-N(C 1-6 Alkyl)-(C 1-6 Alkylene)-*** or -(C 1-9 Alkylene)-N(H)C(O)-[(CH2CH2-O-] 7-15 -(C 1-6 Alkylene)-N(C 1-6 Alkyl)-(C 1-6 Alkylene)-***, where *** is the point of attachment to A 2 of.

[0385] In certain embodiments, L is -N(H)-[(C 2-4 Alkylene)-O-] 2-6 -(C 1-6 Alkylene)-N(H)-***, -N(H)-[(C 2-4 Alkylene)-O-] 7-15 -(C 1-6 Alkylene)-N(H)-***, -N(C 1-6 Alkyl)-[(C 2-4 Alkylene)-O-] 2-6 -(C 1-6 Alkylene)-N(H)-***, -N(C 1-6 Alkyl)-[(C 2-4 Alkylene)-O-] 7-15 -(C 1-6 Alkylene)-N(H)-***, -N(C 1-6 Alkyl)-[(C 2-4 Alkylene)-O-] 2-6 -(C 1-6 Alkylene)-N(C 1-6 Alkyl)-*** or -N(C 1-6 Alkyl)-[(C 2-4 Alkylene)-O-] 7-15 -(C 1-6 Alkylene)-N(C 1-6 Alkyl)-***, where *** is the point of attachment to A 2 of.

[0386] In certain embodiments, L is -N(H)-[CH2CH2-O-] 2-6 -(C 1-6Alkylene)-N(H)-***, -N(H)-[CH2CH2-O-] 7-15 -(C 1-6 Alkylene)-N(H)-***, -N(C 1-6 alkyl)-[CH2CH2-O-] 2-6 -(C 1-6 Alkylene)-N(H)-***, -N(C 1-6 alkyl)-[CH2CH2-O-] 7-15 -(C 1-6 Alkylene)-N(H)-***, -N(C 1-6 alkyl)-[CH2CH2-O-] 2-6 -(C 1-6 Alkylene)-N(C 1-6 Alkyl)-*** or -N(C 1-6 alkyl)-[CH2CH2-O-] 7-15 -(C 1-6 Alkylene)-N(C 1-6 Alkyl)-***, where *** is 2 connection point.

[0387] In some embodiments, L is one of the following:

[0388]

[0389]

[0390]

[0391]

[0392]

[0393]

[0394]

[0395]

[0396]

[0397]

[0398]

[0399] The virtual keys indicate the connection points.

[0400] In certain embodiments, L is -C(H)(R 100 )-、-C(R100 ) 2-, O, -N(R 101 ) -, -S(O)2-, optionally substituted C 3-7 subcycloalkyl, optionally substituted C 4-7 subcycloalkenyl or optionally substituted 3- to 7-membered heterosubcycloalkyl containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur; wherein R 100 independently represents hydrogen, halogen, C 1-6 alkyl or C 3-6 cycloalkyl each time it appears, and R 101 is hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl. In certain embodiments, R 100 independently represents hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or cyclopentyl each time it appears. In certain embodiments, R 101 is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or cyclopentyl.

[0401] In certain embodiments, L is -CH2-Y 20 -, -C(H)(R 100 )-Y 20 -, -C(R 100 )2-Y 20 -, -O-Y 20 -, -N(R 101 )-Y 20 -, -S(O)2-Y 20 -, -C(O)-Y 20 -, -(optionally substituted C 3-7 subcycloalkyl)-Y 20 -, -(optionally substituted C 4-7 subcycloalkenyl)-Y 20 -, -(optionally substituted 3- to 7-membered heterosubcycloalkyl containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur)-Y 20 -, -Y 20 -CH2-, -Y 20 -C(H)(R 100 )-, -Y 20 -C(R 100 )2-, -Y 20 -O-, -Y 20 -N(R 101 )-, -Y 20 -S(O)2-, -Y 20 -C(O)-, -Y 20 -(optionally substituted C 3-7 subcycloalkyl)-, -Y 20 -(optionally substituted C4-7 -substituted cycloalkenylene)-, or -Y 20 -(optionally substituted 3- to 7-membered heterocyclylene containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur); wherein R 100 independently represents, each occurrence, hydrogen, halogen, C 1-6 alkyl, or C 3-6 cycloalkyl, and R 101 is hydrogen, C 1-6 alkyl, or C 3-6 cycloalkyl. In certain embodiments, R 100 independently represents, each occurrence, hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. In certain embodiments, R 101 is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.

[0402] In certain embodiments, L is one of the following:

[0403]

[0404] wherein X 20 , Y 20 and Z 20 are independently -CH2-, -C(H)(R 100 )-, -C(R 100 )2-, O, -N(R 101 )-, -S(O)2-, -C(O)-, optionally substituted C 3-7 cycloalkylene, or optionally substituted C 4-7 cycloalkenylene; wherein R 100 independently represents, each occurrence, hydrogen, halogen, C 1-6 alkyl, or C 3-6 cycloalkyl, and R 101 is hydrogen, C 1-6 alkyl, or C 3-6 cycloalkyl. In certain embodiments, R 100 independently represents, each occurrence, hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. In certain embodiments, R 101 is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.

[0405] In certain embodiments, L is one of the following:

[0406]

[0407] wherein X 20 , Y 20 and Z 20 are independently -C(R 100)- or -N-; wherein R 100 independently represents, each time it appears, hydrogen, halogen, C 1-6 alkyl or C 3-6 cycloalkyl. In certain embodiments, R 100 independently represents, each time it appears, hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or cyclopentyl.

[0408] In certain embodiments, L is -X 20 -Y 20 -Z 20 -, wherein X 20 , Y 20 and Z 20 are independently -CH2-, -C(H)(R 100 ), -C(R 100 )2-, O, -N(R 101 ), -S(O)2-, -C(O)-, optionally substituted C 3-7 subcycloalkyl, optionally substituted C 4-7 subcycloalkenyl or optionally substituted 3- to 7-membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur; wherein R 100 independently represents, each time it appears, hydrogen, halogen, C 1-6 alkyl or C 3-6 cycloalkyl, and R 101 is hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl. In certain embodiments, R 100 independently represents, each time it appears, hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or cyclopentyl. In certain embodiments, R 101 is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or cyclopentyl.

[0409] In certain embodiments, L is -X 20 =Y 20 -Z 21 -, wherein X 20 and Y 20 are independently -C(R 100 ), or -N-, and Z 21 is -CH2-, -C(H)(R 100 ), -C(R 100 )2-, O, -N(R 101 ), -S(O)2-, -C(O)-, optionally substituted C 3-7 subcycloalkyl or optionally substituted C 4-7 subcycloalkenyl; wherein R 100 independently represents, each time it appears, hydrogen, halogen, C1-6 alkyl or C 3-6 cycloalkyl, and R 101 is hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl. In certain embodiments, R 100 independently represents hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or cyclopentyl each time it appears. In certain embodiments, R 101 is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or cyclopentyl.

[0410] In certain embodiments, L is -C≡C-Z 20 -, where Z 20 is -CH2-, -C(H)(R 100 )-, -C(R 100 )2-, O, -N(R 101 )-, -S(O)2-, -C(O)-, optionally substituted C 3-7 subcycloalkyl or optionally substituted C 4-7 subcycloalkenyl; wherein R 100 independently represents hydrogen, halogen, C 1-6 alkyl or C 3-6 cycloalkyl each time it appears, and R 101 is hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl. In certain embodiments, R 100 independently represents hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or cyclopentyl each time it appears. In certain embodiments, R 101 is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or cyclopentyl.

[0411] In certain embodiments, L is one of the following:

[0412]

[0413] wherein X 20 , Y 20 and Z 20 are independently -CH2-, -C(H)(R 100 )-, -C(R 100 )2-, O, -N(R 101 )-, -S(O)2-, -C(O)-, optionally substituted C 3-7 subcycloalkyl, optionally substituted C 4-7 subcycloalkenyl or optionally substituted 3- to 7-membered heterosubcyclic group containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur; wherein R 100 independently represents hydrogen, halogen, C1-6 alkyl or C 3-6 cycloalkyl, and R 101 is hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl. In certain embodiments, R 100 independently represents, each time it appears, hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or cyclopentyl. In certain embodiments, R 101 is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or cyclopentyl.

[0414] In certain embodiments, L is one of the following:

[0415]

[0416]

[0417] wherein V 20 , W 20 , X 20 , Y 20 and Z 20 are independently -CH2-, -C(H)(R 100 ), -C(R 100 )2-, O, -N(R 101 ), -S(O)2-, -C(O)-, optionally substituted C 3-7 subcycloalkyl, optionally substituted C 4-7 subcycloalkenyl or optionally substituted 3- to 7-membered heterosubcyclic group containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur; wherein R 100 independently represents, each time it appears, hydrogen, halogen, C 1-6 alkyl or C 3-6 cycloalkyl, and R 101 is hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl. In certain embodiments, R 100 independently represents, each time it appears, hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or cyclopentyl. In certain embodiments, R 101 is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or cyclopentyl.

[0418] In certain embodiments, L is one of the following:

[0419]

[0420] wherein W 20 , X 20 , Y 20 and Z 20 are independently -C(R100 )- or -N-; where R 100 independently represents hydrogen, halogen, C 1-6 alkyl or C 3-6 cycloalkyl each time it appears. In certain embodiments, R 100 independently represents hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or cyclopentyl each time it appears.

[0421] In certain embodiments, L is one of the following:

[0422]

[0423] where W 20 , X 20 , Y 20 and Z 20 are independently -C(R 100 )- or -N-; where R 100 independently represents hydrogen, halogen, C 1-6 alkyl or C 3-6 cycloalkyl each time it appears. In certain embodiments, R 100 independently represents hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or cyclopentyl each time it appears.

[0424] In certain embodiments, L is one of the following:

[0425]

[0426]

[0427] where U, V, W, X, Y and Z are independently -CH2-, -C(H)(R 100 ), -C(R 100 )2-, O, -N(R 101 ), -S(O)2-, -C(O)-, optionally substituted C 3-7 subcycloalkyl, optionally substituted C 4-7 subcycloalkenyl or optionally substituted 3- to 7-membered heterosubcyclic group containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur; where R 100 independently represents hydrogen, halogen, C 1-6 alkyl or C 3-6 cycloalkyl each time it appears; R 101 is hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl; and the dashed bond indicates the point of attachment. In certain embodiments, R 100 independently represents hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or cyclopentyl each time it appears. In certain embodiments, R101 is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or cyclopentyl.

[0428] In certain embodiments, L is one of the following:

[0429]

[0430] wherein X, Y and Z are independently -C(R 100 )- or -N-; V and W are independently -CH2-, -C(H)(R 100 )-, -C(R 100 )2-, O, -N(R 101 )-, -S(O)2-, -C(O)-, optionally substituted C 3-7 subcycloalkyl, optionally substituted C 4-7 subcycloalkenyl or optionally substituted 3- to 7-membered heterosubcyclic group containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur; wherein R 100 independently represents hydrogen, halogen, C 1-6 alkyl or C 3-6 cycloalkyl each time it appears; R 101 is hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl; and the dashed bond indicates the point of attachment. In certain embodiments, R 100 independently represents hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or cyclopentyl each time it appears. In certain embodiments, R 101 is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or cyclopentyl.

[0431] In certain embodiments, L is one of the following:

[0432]

[0433] wherein W, X, Y and Z are independently -C(R 100 )- or -N-; V is -CH2-, -C(H)(R 100 )-, -C(R 100 )2-, O, -N(R 101 )-, -S(O)2-, -C(O)-, optionally substituted C 3-7 subcycloalkyl, optionally substituted C 4-7 subcycloalkenyl or optionally substituted 3- to 7-membered heterosubcyclic group containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur; wherein R 100 independently represents hydrogen, halogen, C 1-6 alkyl or C 3-6 cycloalkyl each time it appears; R 101 is hydrogen, C1-6 alkyl or C 3-6 cycloalkyl; and the dashed bond indicates the point of attachment. In certain embodiments, R 100 independently represents, each time it appears, hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. In certain embodiments, R 101 is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.

[0434] In certain embodiments, L is one of the following:

[0435]

[0436]

[0437] wherein T, U, V, W, X, Y, and Z are independently -CH2-, -C(H)(R 100 ), -C(R 100 )2-, O, -N(R 101 ), -S(O)2-, -C(O)-, optionally substituted C 3-7 subcycloalkyl, optionally substituted C 4-7 subcycloalkenyl, or optionally substituted 3- to 7-membered heterosubcyclic group containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur; wherein R 100 independently represents, each time it appears, hydrogen, halogen, C 1-6 alkyl or C 3-6 cycloalkyl; R 101 is hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl; and the dashed bond indicates the point of attachment. In certain embodiments, R 100 independently represents, each time it appears, hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. In certain embodiments, R 101 is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.

[0438] In certain embodiments, L is one of the following:

[0439]

[0440] wherein W, X, Y, and Z are independently -C(R 100 ), or -N-; U and V are independently -CH2-, -C(H)(R 100 ), -C(R 100 )2-, O, -N(R 101 ), -S(O)2-, -C(O)-, optionally substituted C 3-7 subcycloalkyl, optionally substituted C4-7 A subcycloalkenyl group or an optionally substituted 3- to 7-membered heterocycloalkylidene group containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur; R 100 Independently represents, each occurrence, hydrogen, halogen, C 1-6 alkyl or C 3-6 cycloalkyl; R 101 is hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl; and the dashed bond indicates the point of attachment. In certain embodiments, R 100 Independently represents, each occurrence, hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or cyclopentyl. In certain embodiments, R 101 is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or cyclopentyl.

[0441] In certain embodiments, L is one of the following:

[0442]

[0443] wherein X, Y and Z are independently -C(R 100 )- or -N-; U, V and W are independently -CH2-, -C(H)(R 100 )-, -C(R 100 )2-, O, -N(R 101 )-, -S(O)2-, -C(O)-, an optionally substituted C 3-7 subcycloalkyl, an optionally substituted C 4-7 subcycloalkenyl or an optionally substituted 3- to 7-membered heterocycloalkylidene group containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur; wherein R 100 Independently represents, each occurrence, hydrogen, halogen, C 1-6 alkyl or C 3-6 cycloalkyl; R 101 is hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl; and the dashed bond indicates the point of attachment. In certain embodiments, R 100 Independently represents, each occurrence, hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or cyclopentyl. In certain embodiments, R 101 is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or cyclopentyl.

[0444] In certain embodiments, L is one of the following:

[0445]

[0446]

[0447] wherein

[0448] the variables m, n, o, p, and q are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0449] In certain embodiments, L is one of the following:

[0450]

[0451]

[0452]

[0453]

[0454]

[0455]

[0456]

[0457] where any m or n is independently 0, 1, 2, 3, 4, 5, or 6; and any X is H or F.

[0458] In certain embodiments, L is one of the following:

[0459]

[0460]

[0461]

[0462]

[0463] where any m or n is independently 0, 1, 2, 3, 4, 5, or 6. In certain embodiments, L is one of the following:

[0464]

[0465]

[0466]

[0467] where any m or n is independently 0, 1, 2, 3, 4, 5, or 6. In certain embodiments, L is one of the following:

[0468]

[0469]

[0470]

[0471]

[0472] In certain embodiments, L is one of the following:

[0473]

[0474]

[0475]

[0476]

[0477]

[0478]

[0479] In certain embodiments, L has the formula -(C 0-12 alkylene)-(optionally substituted 3-40 membered heteroalkylene)-(C 0-12 alkylene)-. In certain embodiments, L is C 4-14 alkylene. In certain embodiments, L is -(CH2) 6-10 -.

[0480] In certain embodiments, L is -CH2CH2(OCH2CH2)-***, -CH2CH2(OCH2CH2)2-***, -CH2CH2(OCH2CH2)3-***, -CH2CH2(OCH2CH2)4-***, -CH2CH2(OCH2CH2)5-***, -CH2CH2(OCH2CH2)6-***, -CH2CH2(OCH2CH2)7-***, -CH2CH2(OCH2CH2)8-***, -CH2CH2(OCH2CH2)9-***, -CH2CH2(OCH2CH2) 10 -***, -CH2CH2(OCH2CH2) 11 -***, -CH2CH2(OCH2CH2) 12 -***, -CH2CH2(OCH2CH2) 13 -***, -CH2CH2(OCH2CH2) 14 -***, -CH2CH2(OCH2CH2) 15 -*** or -CH2CH2(OCH2CH2) 16-20-***, wherein *** is the connecting point with A 2 of the connecting point.

[0481] In certain embodiments, L is -(C 2-20 alkylene)-(OCH2CH2) 2-4 -(C 0-4 alkylene)-***, -(C 2-20 alkylene)-(OCH2CH2) 5-7 -(C 0-4 alkylene)-***, -(C 2-20 alkylene)-(OCH2CH2) 8-10 -(C 0-4 alkylene)-***, -(C 2-20 alkylene)-(OCH2CH2) 11-13 -(C 0-4 alkylene)-***, -(C 2-20 alkylene)-(OCH2CH2) 14-16 -(C 0-4 alkylene)-***, -(C 2-20 alkylene)-(OCH2CH2) 17-20 -(C 0-4 alkylene)-***, -(C 1-20 alkylene)-(OCH2CH2) 1-10 -(C 0-4 alkylene)-C(O)-*** or -(C 1-20 alkylene)-(OCH2CH2) 11-20 -(C 0-4 alkylene)-C(O)-***, wherein *** is the connecting point with A 2 of the connecting point.

[0482] In certain embodiments, L is -O(CH2CH2O) 2-4 -(C 0-4 alkylene)-***, -O(CH2CH2O) 5-7 -(C 0-4 alkylene)-***, -O(CH2CH2O) 8-10 -(C 0-4 alkylene)-***, -O(CH2CH2O) 11-13 -(C 0-4 alkylene)-***, -O(CH2CH2O) 14-16 -(C 0-4 alkylene)-***, -O(CH2CH2O) 16-20 -(C 0-4 alkylene)-***, -O(CH2CH2O) 2-10-(C 0-4 alkylene)C(O)-*** or -O(CH2CH2O) 11-20 -(C 0-4 alkylene)C(O)-***, where *** is the point of attachment to A 2 .

[0483] In certain embodiments, L is -(C 0-20 alkylene)-(OCH2CH2) 1-10 -(N(C 1-4 alkyl))-***, -(C 0-20 alkylene)-(OCH2CH2) 11-20 -(N(C 1-4 alkyl))-***, -(C 0-20 alkylene)-(CH2CH2O) 1-10 -(C 2-10 alkylene)-(N(C 1-4 alkyl))-(C 0-10 alkylene)-*** or -(C 0-20 alkylene)-(CH2CH2O) 11-20 -(C 2-10 alkylene)-(N(C 1-4 alkyl))-(C 0-10 alkylene)-***, where *** is the point of attachment to A 2 .

[0484] In certain embodiments, L is selected from those groups depicted in the compounds of Table 1 below.

[0485] Exemplary specific compounds

[0486] In certain embodiments, the compound is a compound of Table 1 or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Table 1. In certain embodiments, the compound is a compound selected from Compounds I-1 to I-44 of Table 1. In certain embodiments, the compound is a compound selected from Compounds I-1 to I-44 of Table 1 or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound selected from Compounds I-1 to I-199 of Table 1. In certain embodiments, the compound is a compound selected from Compounds I-1 to I-199 of Table 1 or a pharmaceutically acceptable salt thereof.

[0487] Table 1.

[0488]

[0489]

[0490]

[0491]

[0492]

[0493]

[0494]

[0495]

[0496]

[0497]

[0498]

[0499]

[0500]

[0501]

[0502]

[0503]

[0504]

[0505]

[0506]

[0507]

[0508]

[0509]

[0510]

[0511]

[0512]

[0513]

[0514]

[0515]

[0516]

[0517]

[0518]

[0519]

[0520]

[0521]

[0522]

[0523]

[0524]

[0525]

[0526]

[0527]

[0528]

[0529]

[0530]

[0531]

[0532]

[0533]

[0534]

[0535]

[0536]

[0537]

[0538]

[0539]

[0540]

[0541]

[0542]

[0543]

[0544]

[0545]

[0546]

[0547]

[0548]

[0549]

[0550]

[0551]

[0552]

[0553]

[0554]

[0555]

[0556]

[0557]

[0558]

[0559]

[0560]

[0561]

[0562]

[0563]

[0564]

[0565]

[0566]

[0567]

[0568]

[0569]

[0570]

[0571]

[0572]

[0573]

[0574]

[0575]

[0576]

[0577]

[0578]

[0579]

[0580]

[0581]

[0582]

[0583]

[0584]

[0585]

[0586]

[0587]

[0588]

[0589]

[0590]

[0591]

[0592]

[0593]

[0594]

[0595]

[0596]

[0597]

[0598]

[0599]

[0600]

[0601]

[0602]

[0603]

[0604]

[0605]

[0606]

[0607]

[0608]

[0609]

[0610]

[0611]

[0612]

[0613]

[0614]

[0615]

[0616]

[0617]

[0618]

[0619]

[0620]

[0621]

[0622]

[0623]

[0624]

[0625]

[0626]

[0627]

[0628]

[0629]

[0630]

[0631]

[0632]

[0633]

[0634]

[0635]

[0636]

[0637]

[0638]

[0639]

[0640]

[0641]

[0642]

[0643]

[0644]

[0645]

[0646] Synthesis method

[0647] The following synthetic procedures illustrate methods for preparing the compounds described herein. The procedures are provided for purposes of illustration of the invention and are not intended to limit the scope or spirit of the invention. The starting materials shown in the procedures may be obtained from commercial sources or may be prepared based on procedures described in the literature.

[0648] In the procedures, those skilled in the art of organic synthesis will understand that the functional groups present on the various parts of the molecule should be compatible with the proposed reagents and reactions. Substituents that are incompatible with the reaction conditions will be apparent to those skilled in the art and will thus indicate alternative methods (e.g., use of protecting groups or alternative reactions). Protecting group chemistry and strategies are well known, such as those described in “Protecting Groups in Organic Synthesis”, T.W. Greene and P.G.M. Wuts, 3rd Edition, John Wiley & Sons, 1999, the entire content of which is hereby incorporated by reference.

[0649] The synthetic route illustrated in Scheme 1 is a general method for preparing Compound F. The reaction of carboxylic acid A with amine B under amide coupling conditions gives amide C. Removal of the protecting group (Pg) from Compound C gives Compound D. Pg can be, for example, a Boc protecting group, which can be removed by treating the compound with trifluoroacetic acid. The coupling of Compound D with Compound E (such as a nucleophilic aromatic substitution reaction when X is an amino group and the leaving group in Compound E is chlorine) gives the final Compound F.

[0650] Scheme 1.

[0651]

[0652] The modular synthetic pathways illustrated in Scheme 1 can be readily modified to provide additional compounds by performing functional group transformations on intermediate and / or final compounds. Such functional group transformations are well known in the art and are described, for example, in Comprehensive Organic Synthesis (Eds. B.M. Trost and I. Fleming, 1991-1992); Organic Synthesis, 3rd Edition (Michael B. Smith, Wavefunction, Inc., Irvine: 2010); Modern Methods of Organic Synthesis, 4th Edition (William Carruthers and Iain Coldham, Cambridge University Press, Cambridge: 2004); March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 8th Edition, (Michael B. Smith, John Wiley & Sons, New York: 2020); and Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 3rd Edition (Ed. Richard C. Larock, John Wiley & Sons, New York: 2018). Protecting group strategies can be employed as appropriate to accommodate the different functional groups in the molecules used in the synthetic pathways. Protecting group chemistry and strategies are described, for example, in Protecting Groups in Organic Synthesis, 3rd Edition, T.W. Greene and P.G.M. Wuts, John Wiley & Sons, 1999 and Greene's Protective Groups in Organic Synthesis, 5th Edition, (Peter G.M. Wuts, John Wiley & Sons: 2014).

[0653] II. Therapeutic Applications

[0654] The heterobifunctional compounds described herein, such as the compounds of Formula I, Formula II or other compounds in Section I, provide a therapeutic benefit to patients suffering from cancer. Accordingly, one aspect of the present invention provides a method of treating cancer. The method comprises administering to a patient in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula I, Formula II or other compounds in Section I, to treat cancer. In certain embodiments, the compound is a compound of Formula I. In certain embodiments, a particular compound of Formula I is a compound defined by one of the embodiments described above.

[0655] Cancer

[0656] In certain embodiments, the cancer is ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, prostate cancer, testicular cancer, breast cancer, brain cancer, lung cancer, oral cancer, esophageal cancer, head and neck cancer, gastric cancer, colon cancer, rectal cancer, skin cancer, sebaceous gland cancer, bile duct cancer and gallbladder cancer, liver cancer, pancreatic cancer, bladder cancer, urinary tract cancer, kidney cancer, eye cancer, thyroid cancer, lymphoma or leukemia. In certain embodiments, the cancer is prostate cancer.

[0657] In certain embodiments, the cancer is squamous cell carcinoma, lung cancer (including small cell lung cancer, non-small cell lung cancer), vulvar cancer, thyroid cancer, lung adenocarcinoma and lung squamous cell carcinoma, peritoneal cancer, hepatocellular carcinoma, gastric cancer (including gastrointestinal cancer), pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial cancer or uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, liver cancer, anal cancer, penile cancer and head and neck cancer. In certain embodiments, the cancer is at least one selected from the group consisting of: ALL, T-lineage acute lymphoblastic leukemia (T-ALL), T-lineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, Pre-B ALL, Pre-B lymphoma, large B-cell lymphoma, Burkitts Lymphoma, B-cell ALL, Philadelphia chromosome positive ALL, Philadelphia chromosome positive CML, lymphoma, leukemia, multiple myeloma, myeloproliferative disease, large B-cell lymphoma or B-cell lymphoma.

[0658] In certain embodiments, the cancer is a solid tumor or leukemia. In certain other embodiments, the cancer is colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, lung cancer, leukemia, bladder cancer, stomach cancer, cervical cancer, testicular cancer, skin cancer, rectal cancer, thyroid cancer, kidney cancer, uterine cancer, esophageal cancer, liver cancer, acoustic neuroma, oligodendroglioma, meningioma, neuroblastoma or retinoblastoma. In certain other embodiments, the cancer is small cell lung cancer, non-small cell lung cancer, melanoma, central nervous system tissue cancer, brain cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, cutaneous B-cell lymphoma or diffuse large B-cell lymphoma. In certain other embodiments, the cancer is breast cancer, colon cancer, small cell lung cancer, non-small cell lung cancer, prostate cancer, kidney cancer, ovarian cancer, leukemia, melanoma or central nervous system tissue cancer. In certain other embodiments, the cancer is colon cancer, small cell lung cancer, non-small cell lung cancer, kidney cancer, ovarian cancer, kidney cancer or melanoma.

[0659] In certain embodiments, the cancer is fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, epithelioma, glioma, astrocytoma, medulloblastoma or hemangioblastoma.

[0660] In certain embodiments, the cancer is neuroblastoma, meningioma, hemangiopericytoma, multiple brain metastases, glioblastoma multiforme, glioblastoma, brainstem glioma, malignant brain tumor with poor prognosis, malignant glioma, anaplastic astrocytoma, anaplastic oligodendroglioma, neuroendocrine tumor, rectal adenocarcinoma, Dukes C and D colorectal cancer, unresectable colorectal cancer, metastatic hepatocellular carcinoma, Kaposi's sarcoma, karyotypic acute myeloid leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, cutaneous B-cell lymphoma, diffuse large B-cell lymphoma, low-grade follicular lymphoma, metastatic melanoma, local melanoma, malignant mesothelioma, malignant pleural effusion mesothelioma syndrome, peritoneal carcinoma, papillary serous carcinoma, gynecological sarcoma, soft tissue sarcoma, scleroderma, cutaneous vasculitis, Langerhans cell histiocytosis, leiomyosarcoma, progressive osseous heteroplasia, hormone-refractory prostate cancer, resected high-risk soft tissue sarcoma, unresectable hepatocellular carcinoma, Waldenstrom's macroglobulinemia, smoldering myeloma, indolent myeloma, fallopian tube cancer, androgen-independent prostate cancer, androgen-dependent stage IV non-metastatic prostate cancer, hormone-non-sensitive prostate cancer, chemotherapy-non-sensitive prostate cancer, castration-resistant prostate cancer, castration-resistant metastatic prostate cancer, papillary thyroid cancer, follicular thyroid cancer, medullary thyroid cancer, or leiomyoma.

[0661] In certain embodiments, the cancer is bone cancer, pancreatic cancer, skin cancer, head or neck cancer, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, anal cancer, stomach cancer, gastrointestinal (stomach, colorectal and duodenum), uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's Disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myelogenous leukemia, lymphocytic lymphoma, bladder cancer, renal or ureteral cancer, renal cell carcinoma, renal pelvic carcinoma, non-Hodgkin's lymphoma, spinal cord tumor, brainstem glioma, pituitary adenoma, adrenocortical carcinoma, gallbladder cancer, multiple myeloma, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastoma, or a combination of one or more of the foregoing cancers.

[0662] In certain embodiments, the cancer is hepatocellular carcinoma, ovarian cancer, ovarian epithelial cancer, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; intrahepatic cholangiocarcinoma; soft tissue and bone synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing sarcoma; anaplastic thyroid cancer; adrenocortical adenoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma; gastrointestinal / gastric (GIST) cancer; lymphoma; head and neck squamous cell carcinoma (SCCHN); salivary gland cancer; glioblastoma or brain cancer; neurofibromatosis-1 associated malignant peripheral nerve sheath tumor (MPNST); Waldenström macroglobulinemia; or medulloblastoma.

[0663] In certain embodiments, the cancer is hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial cancer, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), intrahepatic cholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenocortical adenoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioblastoma, neurofibromatosis-1 associated malignant peripheral nerve sheath tumor (MPNST), Waldenström macroglobulinemia, or medulloblastoma.

[0664] In certain embodiments, the cancer is a solid tumor, such as a sarcoma, carcinoma, or lymphoma. In certain embodiments, the cancer is renal cancer; hepatocellular carcinoma (HCC) or hepatoblastoma or liver cancer; melanoma; breast cancer; colorectal carcinoma or colorectal cancer; colon cancer; rectal cancer; anal cancer; lung cancer, such as non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC); ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; intrahepatic cholangiocarcinoma; soft tissue and bone synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing sarcoma; anaplastic thyroid cancer; adrenocortical carcinoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma; gastrointestinal / gastric (GIST) cancer; lymphoma; head and neck squamous cell carcinoma (SCCHN); salivary gland cancer; glioblastoma or brain cancer; neurofibromatosis-1 associated malignant peripheral nerve sheath tumor (MPNST); Waldenström macroglobulinemia; or medulloblastoma.

[0665] In certain embodiments, the cancer is renal cell carcinoma, hepatocellular carcinoma (HCC), hepatoblastoma, colorectal carcinoma, colorectal cancer, colon cancer, rectal cancer, anal cancer, ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), intrahepatic cholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioblastoma, brain cancer, neurofibromatosis-1 associated malignant peripheral nerve sheath tumor (MPNST), Waldenström macroglobulinemia, or medulloblastoma.

[0666] In certain embodiments, the cancer is hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), intrahepatic cholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioblastoma, neurofibromatosis-1 associated malignant peripheral nerve sheath tumor (MPNST), Waldenström macroglobulinemia, or medulloblastoma.

[0667] In certain embodiments, the cancer is hepatocellular carcinoma (HCC). In some embodiments, the cancer is hepatoblastoma. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is ovarian cancer or ovarian carcinoma. In some embodiments, the cancer is ovarian epithelial cancer. In some embodiments, the cancer is fallopian tube cancer. In some embodiments, the cancer is papillary serous cystadenocarcinoma. In some embodiments, the cancer is uterine papillary serous carcinoma (UPSC). In some embodiments, the cancer is intrahepatic cholangiocarcinoma. In some embodiments, the cancer is soft tissue and bone synovial sarcoma. In some embodiments, the cancer is rhabdomyosarcoma. In some embodiments, the cancer is osteosarcoma. In some embodiments, the cancer is anaplastic thyroid cancer. In some embodiments, the cancer is adrenocortical carcinoma. In some embodiments, the cancer is pancreatic cancer or pancreatic ductal carcinoma. In some embodiments, the cancer is pancreatic adenocarcinoma. In some embodiments, the cancer is glioblastoma. In some embodiments, the cancer is malignant peripheral nerve sheath tumor (MPNST). In some embodiments, the cancer is neurofibromatosis-1 associated MPNST. In some embodiments, the cancer is Waldenström macroglobulinemia. In some embodiments, the cancer is medulloblastoma.

[0668] Induce Cancer Cell Death

[0669] Another aspect of the present invention provides a method for causing cancer cell death. The method includes contacting cancer cells with an effective amount of a compound described herein, such as a compound of Formula I or Formula II or other compounds in Section I, to cause cancer cell death. In certain embodiments, a particular compound of Formula I or Formula II is a compound defined by one of the embodiments described above.

[0670] In certain embodiments, the cancer cells are selected from ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, prostate cancer, testicular cancer, breast cancer, brain cancer, lung cancer, oral cancer, esophageal cancer, head and neck cancer, gastric cancer, colon cancer, rectal cancer, skin cancer, sebaceous gland cancer, bile duct and gallbladder cancer, liver cancer, pancreatic cancer, bladder cancer, urinary tract cancer, kidney cancer, eye cancer, thyroid cancer, lymphoma, or leukemia. In certain embodiments, the cancer cells are one or more of the cancers recited in the section entitled "Cancer" above. In certain embodiments, the cancer cells are prostate cancer cells.

[0671] Combination therapy

[0672] The compounds useful in the methods of the present invention can be used in combination with one or more additional therapeutic agents useful for treating any disease contemplated herein. These additional therapeutic agents can include compounds that are commercially available or can be synthesized by those skilled in the art. These additional therapeutic agents are known to treat, prevent, or alleviate the symptoms of the diseases or disorders contemplated herein.

[0673] Thus, in certain embodiments, the method further includes administering to a subject an additional therapeutic agent for treating a disease contemplated herein.

[0674] In certain embodiments, administering a compound of the present invention to a subject permits the administration of a lower dose of an additional therapeutic agent compared to the dose of the additional therapeutic agent alone required to achieve a similar result in treating a disease contemplated herein. For example, in certain embodiments, a compound of the present invention enhances the therapeutic activity of an additional therapeutic compound, thereby permitting a lower dose of the additional therapeutic compound to provide the same effect.

[0675] Synergy can be calculated, for example, using a suitable method such as Sigmoid-E maxThe equations (Holford and Scheiner, 1981, Clin. Pharmacokinet. 6:429 - 453), the Loewe additivity equation (Loewe and Muischnek, 1926, Arch. Exp. Pathol Pharmacol. 114:313 - 326), and the median-effect equation (Chou and Talalay, 1984, Adv. Enzyme Regul. 22:27 - 55). Each of the equations mentioned above can be applied to experimental data to generate corresponding graphs to assist in evaluating the effect of drug combinations. The corresponding graphs related to the equations mentioned above are the concentration - effect curve, the isobologram curve, and the combination index curve, respectively.

[0676] In certain embodiments, the compounds of the invention and a therapeutic agent are co - administered to a subject. In other embodiments, the compounds of the invention and a therapeutic agent are co - formulated and co - administered to a subject.

[0677] In certain embodiments, the compound is administered in combination with a second therapeutic agent having anti-cancer activity. In certain embodiments, the second therapeutic agent is mitomycin, tretinoin, ribomustin, gemcitabine, vincristine, etoposide, cladribine, mitobronitol, methotrexate, doxorubicin, carboquone, pentostatin, nitracrine, zinostatin, cetrorelix, letrozole, raltitrexed, daunorubicin, fadrozole, fotemustine, thymalfasin, sobuzoxane, nedaplatin, cytarabine, bicalutamide, vinorelbine, vesnarinone, aminoglutethimide, amsacrine, proglumide, elliptiniumacetate), ketanserin, doxifluridine, etretinate, isotretinoin, streptozocin, nimustine, vindesine, flutamide, drogenil, butocin, carmofur, razoxane, sizofilan, carboplatin, mitolactol, tegafur, ifosfamide, prednimustine, picibanil, levamisole, teniposide, improsulfan, enocitabine, lisuride, oxymetholone, tamoxifen, progesterone, mepitiostane, epitiostanol, formestane, interferon-α, interferon-2α, interferon-β, interferon-γ, colony stimulating factor-1, colony stimulating factor-2, denileukin diftitox, interleukin-2, and luteinizing hormone releasing factor.

[0678] In certain embodiments, the second therapeutic agent is an mTOR inhibitor that inhibits cell proliferation, angiogenesis, and glucose uptake. mTOR inhibitors approved for use in the present invention include everolimus ( Novartis); temsirolimus ( Pfizer); and sirolimus ( Pfizer).

[0679] In certain embodiments, the second therapeutic agent is a poly ADP ribose polymerase (PARP) inhibitor. PARP inhibitors approved for use in the present invention include olaparib ( AstraZeneca); rucaparib ( Clovis Oncology); and niraparib ( Tesaro). Other PARP inhibitors under investigation that can be used in the present invention include talazoparib (MDV3800 / BMN 673 / LT00673, Medivation / Pfizer / Biomarin); veliparib (ABT-888, AbbVie); and BGB-290 (BeiGene, Inc.).

[0680] In certain embodiments, the second therapeutic agent is a phosphatidylinositol 3-kinase (PI3K) inhibitor. PI3K inhibitors approved for use in the present invention include idelalisib ( Gilead). Other PI3K inhibitors under investigation that can be used in the present invention include alpelisib (BYL719, Novartis); taselisib (GDC-0032, Genentech / Roche); pictilisib (GDC-0941, Genentech / Roche); copanlisib (BAY806946, Bayer); duvelisib (formerly IPI-145, Infinity Pharmaceuticals); PQR309 (Piqur Therapeutics, Switzerland); and TGR1202 (formerly RP5230, TG Therapeutics).

[0681] In certain embodiments, the second therapeutic agent is a proteasome inhibitor. Proteasome inhibitors approved for use in the present invention include bortezomib ( Takeda); carfilzomib ( Amgen); and ixazomib ( Takeda).

[0682] In certain embodiments, the second therapeutic agent is a histone deacetylase (HDAC) inhibitor. HDAC inhibitors approved for use in the present invention include vorinostat ( Merck); romidepsin ( Celgene); panobinostat ( Novartis); and belinostat ( Spectrum Pharmaceuticals). Other HDAC inhibitors under investigation that can be used in the present invention include entinostat (SNDX-275, Syndax Pharmaceuticals) (NCT00866333); and chidamide ( HBI-8000, Chipscreen Biosciences, China).

[0683] In certain embodiments, the second therapeutic agent is a CDK inhibitor, such as a CDK 4 / 6 inhibitor. Approved CDK 4 / 6 inhibitors that can be used in the present invention include palbociclib ( Pfizer); and ribociclib ( Novartis). Other CDK 4 / 6 inhibitors under investigation that can be used in the present invention include abemaciclib (Ly2835219, Eli Lilly); and trilaciclib (G1T28, G1 Therapeutics).

[0684] In certain embodiments, the second therapeutic agent is an indoleamine (2,3)-dioxygenase (IDO) inhibitor. IDO inhibitors under investigation that can be used in the present invention include epacadostat (INCB024360, Incyte); indoximod (NLG-8189, NewLink Genetics Corporation); capmanitib (INC280, Novartis); GDC-0919 (Genentech / Roche); PF-06840003 (Pfizer); BMS:F001287 (Bristol-Myers Squibb); Phy906 / KD108 (Phytoceutica); and the enzyme that degrades kynurenine (Kynase, Kyn Therapeutics).

[0685] In certain embodiments, the second therapeutic agent is a growth factor antagonist, such as an antagonist of platelet-derived growth factor (PDGF) or epidermal growth factor (EGF) or its receptor (EGFR). Approved PDGF antagonists that can be used in the present invention include olaratumab ( Eli Lilly). EGFR antagonists approved for use in the present invention include cetuximab ( Eli Lilly); necitumumab ( Eli Lilly); panitumumab ( Amgen); and osimertinib (targeting activated EGFR, AstraZeneca).

[0686] In certain embodiments, the second therapeutic agent is an aromatase inhibitor. Aromatase inhibitors approved for use in the present invention include exemestane ( Pfizer); anastrozole AstraZeneca); and letrozole ( Novartis).

[0687] In certain embodiments, the second therapeutic agent is a hedgehog pathway antagonist. Hedgehog pathway inhibitors approved for use in the present invention include sonidegib ( SunPharmaceuticals); and vismodegib ( Genentech), both of which are used to treat basal cell carcinoma.

[0688] In certain embodiments, the second therapeutic agent is a folate inhibitor. Folate inhibitors approved for use in the present invention include pemetrexed ( Eli Lilly).

[0689] In certain embodiments, the second therapeutic agent is a CC chemokine receptor 4 (CCR4) inhibitor. Investigational CCR4 inhibitors that can be used in the present invention include mogamulizumab ( KyowaHakko Kirin, Japan).

[0690] In certain embodiments, the second therapeutic agent is an isocitrate dehydrogenase (IDH) inhibitor. IDH inhibitors under investigation that can be used in the present invention include AG120 (Celgene; NCT02677922); AG221 (Celgene, NCT02677922; NCT02577406); BAY1436032 (Bayer, NCT02746081); IDH305 (Novartis, NCT02987010).

[0691] In certain embodiments, the second therapeutic agent is an arginase inhibitor. Arginase inhibitors under investigation that can be used in the present invention include AEB1102 (pegylated recombinant arginase, Aeglea Biotherapeutics), which is being investigated in Phase 1 clinical trials for acute myeloid leukemia and myelodysplastic syndromes (NCT02732184) and solid tumors (NCT02561234); and CB-1158 (Calithera Biosciences).

[0692] In certain embodiments, the second therapeutic agent is a glutaminase inhibitor. Glutaminase inhibitors under investigation that can be used in the present invention include CB-839 (Calithera Biosciences).

[0693] In certain embodiments, the second therapeutic agent is an antibody that binds to a tumor antigen, i.e., a protein expressed on the cell surface of tumor cells. Antibodies that bind to tumor antigens that are approved for use in the present invention include rituximab ( Genentech / Biogen Idec); ofatumumab (anti-CD20, GlaxoSmithKline); obinutuzumab (anti-CD20, Genentech); ibritumomab (anti-CD20 and yttrium-90, Spectrum Pharmaceuticals); daratumumab (anti-CD38, Janssen Biotech); dinutuximab (anti-glycolipid GD2, United Therapeutics); trastuzumab (anti-HER2, Genentech); ado-trastuzumab emtansine (anti-HER2, fused with emtansine, Genentech); and pertuzumab (anti-HER2, Genentech); as well as brentuximab vedotin (an anti-CD30 drug conjugate, Seattle Genetics).

[0694] In certain embodiments, the second therapeutic agent is a topoisomerase inhibitor. Topoisomerase inhibitors approved for use in the present invention include irinotecan Merrimack Pharmaceuticals); topotecan ( GlaxoSmithKline). Investigational topoisomerase inhibitors that can be used in the present invention include pixantrone ( CTI Biopharma).

[0695] In certain embodiments, the second therapeutic agent is a nucleoside inhibitor or other therapeutic agent that interferes with normal DNA synthesis, protein synthesis, cell replication, or otherwise inhibits rapidly proliferating cells. Such nucleoside inhibitors or other therapeutic agents include trabectedin (a guanidine alkylating agent, Janssen Oncology); mechlorethamine (an alkylating agent, Aktelion Pharmaceuticals); vincristine ( Eli Lilly; Teva Pharmaceuticals; Talon Therapeutics); temozolomide (an alkylating agent, the prodrug of 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC) , Merck); cytarabine injection (ara-C, an antimetabolic cytidine analogue, Pfizer); lomustine (an alkylating agent, Bristol-Myers Squibb; NextSource Biotechnology); azacitidine (a pyrimidine nucleoside analogue of cytidine, Celgene); omacetaxine mepesuccinate (cephalotaxine ester) (a protein synthesis inhibitor, Teva Pharmaceuticals); asparaginase Erwinia chrysanthemi (an asparagine-depleting enzyme, Lundbeck; EUSAPharma); eribulin mesylate (a microtubule inhibitor, a tubulin-based anti-mitotic agent, Eisai); cabazitaxel (a microtubule inhibitor, a tubulin-based anti-mitotic agent, Sanofi-Aventis); capacetrine (a thymidylate synthase inhibitor, Genentech); bendamustine (a bifunctional nitrogen mustard derivative that is believed to form interstrand DNA cross-links, Cephalon / Teva); ixabepilone (a semi-synthetic analogue of epothilone B, a microtubule inhibitor, a tubulin-based anti-mitotic agent, Bristol-Myers Squibb); nelarabine (a prodrug of a deoxyguanosine analogue, a nucleoside metabolism inhibitor, Novartis); clorafabine (a prodrug of a ribonucleotide reductase inhibitor, a competitive inhibitor of deoxycytidine, Sanofi-Aventis); and trifluridine and tipiracil (a thymidine-based nucleoside analogue and a thymidine phosphorylase inhibitor, Taiho Oncology).

[0696] In certain embodiments, the second therapeutic agent is a platinum-based therapeutic agent, also known as platinums. Platinums cause DNA cross-links, thereby inhibiting DNA repair and / or DNA synthesis, mainly in rapidly proliferating cells, such as cancer cells. Approved platinum-based therapeutic agents that can be used in the present invention include cisplatin ( Bristol-Myers Squibb); carboplatin ( Bristol-Myers Squibb; also Teva; Pfizer); oxaliplatin ( Sanofi-Aventis); and nedaplatin ( Shionogi). Other platinum-based therapeutic agents that have undergone clinical testing and can be used in the present invention include picoplatin (Poniard Pharmaceuticals); and satraplatin (JM-216, Agennix).

[0697] In certain embodiments, the second therapeutic agent is a taxane compound that causes microtubule disruption necessary for cell division. Taxane compounds approved for use in the present invention include paclitaxel ( Bristol-Myers Squibb), docetaxel ( Sanofi-Aventis; Sun Pharmaceutical), albumin-bound paclitaxel ( Abraxis / Celgene) and cabazitaxel ( Sanofi-Aventis). Other taxane compounds that have undergone clinical testing and can be used in the present invention include SID530 (SK Chemicals, Co.) (NCT00931008).

[0698] In certain embodiments, the second therapeutic agent is an inhibitor of anti-apoptotic proteins such as BCL-2. Anti-apoptotic agents approved for use in the present invention include venetoclax ( AbbVie / Genentech); and blinatumomab ( Amgen). Other therapeutic agents targeting apoptotic proteins that have undergone clinical testing and can be used in the present invention include navitoclax (ABT-263, Abbott), BCL-2 inhibitor (NCT02079740).

[0699] In certain embodiments, the second therapeutic agent is a selective estrogen receptor modulator (SERM) that interferes with the synthesis or activity of estrogen. SERMs approved for use in the present invention include raloxifene ( Eli Lilly).

[0700] In certain embodiments, the second therapeutic agent is an inhibitor of the interaction between the two major p53 inhibitory proteins MDMX and MDM2. Investigational inhibitors of p53 inhibitory proteins that can be used in the present invention include ALRN-6924 (Aileron), a stapled peptide that equivalently binds and disrupts the interactions of MDMX and MDM2 with p53. ALRN-6924 is currently being evaluated in clinical trials for the treatment of AML, advanced myelodysplastic syndrome (MDS), and peripheral T-cell lymphoma (PTCL) (NCT02909972; NCT02264613).

[0701] In certain embodiments, the second therapeutic agent is an inhibitor of transforming growth factor-β (TGF-β or TGFβ). Investigational TGF-β protein inhibitors that can be used in the present invention include NIS793 (Novartis), an anti-TGF-β antibody that is being tested clinically for the treatment of various cancers including breast cancer, lung cancer, hepatocellular carcinoma, colorectal cancer, pancreatic cancer, prostate cancer, and renal cancer (NCT02947165). In some embodiments, the TGF-β protein inhibitor is fresolimumab (GC1008; Sanofi-Genzyme), which is being investigated for melanoma (NCT00923169), renal cell carcinoma (NCT00356460), and non-small cell lung cancer (NCT02581787). Additionally, in some embodiments, the additional therapeutic agent is a TGF-β capture agent, such as described by Connolly et al. (2012) Int'l J. Biological Sciences 8:964-978. One therapeutic compound currently in clinical trials for the treatment of solid tumors is M7824 (Merck KgaA - formerly MSB0011459X), a bispecific anti-PD-L1 / TGFβ capture compound (NCT02699515); and (NCT02517398). M7824 consists of a fully human IgG1 antibody against PD-L1 that is fused to the extracellular domain of the human TGF-β receptor II, thus serving as a TGFβ "capture agent".

[0702] In certain embodiments, the second therapeutic agent is a cancer vaccine. In some embodiments, the cancer vaccine is selected from sipuleucel-T ( Dendreon / Valeant Pharmaceuticals), approved for the treatment of asymptomatic or minimally symptomatic metastatic castration-resistant (hormone-refractory) prostate cancer; and talimogene laherparepvec ( BioVex / Amgen, formerly known as T-VEC), an approved oncolytic virus therapy for the treatment of unresectable cutaneous, subcutaneous, and nodal lesions in melanoma. In some embodiments, the additional therapeutic agent is selected from oncolytic virus therapies such as pexastimogene devacirepvec (PexaVec / JX-594, SillaJen / formerly Jennerex Biotherapeutics), a thymidine kinase (TK)-deficient vaccinia virus engineered to express GM-CSF for the treatment of hepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312); pelareorep ( Oncolytics Biotech), a variant of reovirus, a respiratory enteric orphan virus that cannot replicate in cells without RAS activation in multiple cancers, including colorectal cancer (NCT01622543), prostate cancer (NCT01619813), head and neck squamous cell carcinoma (NCT01166542), pancreatic adenocarcinoma (NCT00998322), and non-small cell lung cancer (NSCLC) (NCT00861627); enadenotucirev (NG-348, PsiOxus, formerly known as ColoAd1), an adenovirus engineered to express full-length CD80 and antibody fragments specific for the T cell receptor CD3 protein in ovarian cancer (NCT02028117), metastatic or advanced epithelial tumors (such as colorectal cancer, bladder cancer, head and neck squamous cell carcinoma, and salivary gland cancer) (NCT02636036); ONCOS-102 (Targovax / formerly known as Oncos), an adenovirus engineered to express GM-CSF in melanoma (NCT03003676) and peritoneal disease, colorectal cancer, or ovarian cancer (NCT02963831); GL-ONC1 (GLV-1h68 / GLV-1h153, Genelux GmbH), a vaccinia virus engineered to express β-galactosidase (β-gal) / β-glucuronidase or β-gal / human sodium iodide symporter (hNIS) and being studied in peritoneal metastatic cancer (NCT01443260), fallopian tube cancer, ovarian cancer (NCT02759588); or CG0070 (Cold Genesys), an adenovirus engineered to express GM-CSF in bladder cancer (NCT02365818).

[0703] In certain embodiments, the second therapeutic agent is an immune checkpoint inhibitor selected from a PD-1 antagonist, a PD-L1 antagonist, or a CTLA-4 antagonist. In some embodiments, the compounds or pharmaceutically acceptable salts thereof disclosed herein are administered in combination with: nivolumab (an anti-PD-1 antibody, Bristol-Myers Squibb); pembrolizumab (an anti-PD-1 antibody, Merck); ipilimumab (an anti-CTLA-4 antibody, Bristol-Myers Squibb); durvalumab (an anti-PD-L1 antibody, AstraZeneca); or atezolizumab (an anti-PD-L1 antibody, Genentech). Other immune checkpoint inhibitors suitable for the present invention include REGN2810 (Regeneron), an anti-PD-1 antibody being tested in patients with basal cell carcinoma (NCT03132636), NSCLC (NCT03088540), cutaneous squamous cell carcinoma (NCT02760498), lymphoma (NCT02651662), and melanoma (NCT03002376); pidilizumab (CureTech), also known as CT-011, an antibody that binds to PD-1 and is in clinical trials for diffuse large B-cell lymphoma and multiple myeloma; avelumab ( Pfizer / Merck KGaA, also known as MSB0010718C), a fully human IgG1 anti-PD-L1 antibody in clinical trials for non-small cell lung cancer, Merkel cell carcinoma, mesothelioma, solid tumors, renal cancer, ovarian cancer, bladder cancer, head and neck cancer, and gastric cancer; and PDR001 (Novartis), an inhibitory antibody that binds to PD-1 and is in clinical trials for non-small cell lung cancer, melanoma, triple-negative breast cancer, and advanced or metastatic solid tumors. Tremelimumab (CP-675,206; Astrazeneca) is a fully human monoclonal antibody against CTLA-4 that has been studied in clinical trials for various indications, including: mesothelioma, colorectal cancer, renal cancer, breast cancer, lung cancer and non-small cell lung cancer, pancreatic ductal adenocarcinoma, pancreatic cancer, germ cell cancer, head and neck squamous cell carcinoma, hepatocellular carcinoma, prostate cancer, endometrial cancer, liver metastases, liver cancer, large B-cell lymphoma, ovarian cancer, cervical cancer, metastatic anaplastic thyroid cancer, urothelial cancer, fallopian tube cancer, multiple myeloma, bladder cancer, soft tissue sarcoma, and melanoma. AGEN-1884 (Agenus) is an anti-CTLA4 antibody being studied in a Phase 1 clinical trial for advanced solid tumors (NCT02694822).

[0704] Another aspect of the present invention provides the use of the compounds described herein (such as compounds of Formula I, Formula II, or other compounds in Section I) in the manufacture of a medicament. In certain embodiments, the medicament is for treating the diseases described herein, such as cancer.

[0705] Another aspect of the present invention provides the use of the compounds described herein (such as compounds of Formula I, Formula II or other compounds in Section I) for the treatment of medical diseases, such as the diseases described herein (e.g., cancer).

[0706] Evaluate Cell Growth Inhibition in HEK293 Cells and HeLa Cells

[0707] The ability of a compound to inhibit the proliferation of HEK293 cells or HeLa cells can be evaluated according to the following procedure. HEK293 and HeLa cells are cultured in DMEM medium supplemented with 10% fetal bovine serum and 1% Penn / Strep. The cells are seeded at 500 cells / well in 25 μL of complete medium in white 384-well plates. After seeding, the plates are spun at 300 × g for three minutes and cultured at 37 °C and 5% CO2 in a humidified tissue culture incubator. After 24 hours, the compounds are titrated in 100% DMSO and diluted in complete cell medium. A 25 μL aliquot of the compound / media mixture is added to the cells to bring the total volume in the wells to 50 μL. DMSO alone is used as a negative control. The plates are then spun at 300 × g for three minutes and stored at 37 °C and 5% CO2 for three days. On Day 0 and Day 3 of compound treatment, cell viability is quantified using CellTiter-Glo 2.0 reagent (Promega). After equilibrating the microplate at room temperature for 30 minutes, 25 μL of CellTiter-Glo 2.0 reagent is dispensed into each well to bring the total volume to 75 μL. The plates are mixed on a shaker at 500 rpm for 2 minutes and then incubated at room temperature for 10 minutes. After a quick spin, the luminescence readings are measured using an EnVision plate reader. The data are normalized against the DMSO-treated Day 0 and Day 3 readings. A four-parameter non-linear regression curve fit is applied to the dose-response data in GraphPad Prism data analysis software to determine the half-maximal growth inhibitory concentration (GI 50 ).

[0708] III. Pharmaceutical Compositions and Administration Considerations

[0709] As indicated above, the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of one or more of the compounds described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and / or diluents. The pharmaceutical compositions can be specially formulated for administration in solid or liquid form, including those adapted for: (1) oral administration, e.g., drenches (aqueous or non-aqueous solutions or suspensions), tablets (e.g., those designed for buccal, sublingual, and systemic absorption), boluses, powders, granules, pastes applied to the tongue; (2) parenteral administration, e.g., by subcutaneous, intramuscular, intravenous, or epidural injection, as, for example, sterile solutions or suspensions or sustained release formulations; (3) topical application, e.g., as creams, ointments, or controlled release patches or sprays applied to the skin; (4) intravaginal or rectal, e.g., as pessaries, creams, or foams; (5) sublingual; (6) ophthalmic; (7) transdermal; or (8) nasal. In certain embodiments, the present invention provides a pharmaceutical composition comprising a compound described herein (e.g., a compound of Formula I) and a pharmaceutically acceptable carrier.

[0710] As used herein, the phrase "therapeutically effective amount" means an amount of a compound, material, or composition comprising a compound of the present invention that is effective to produce some desired therapeutic effect at least in a subset of cells of an animal at a reasonable benefit / risk ratio applicable to any medical treatment.

[0711] The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and / or dosage forms that, within the scope of reasonable medical judgment, are suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0712] Wetting agents, emulsifying agents, and lubricants (such as sodium lauryl sulfate and magnesium stearate), as well as coloring agents, release agents, coating agents, sweetening agents, flavoring agents, and perfuming agents, preservatives, and antioxidants may also be present in the compositions.

[0713] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; (2) oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, etc.; and (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0714] The formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, and / or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any method well known in the art of pharmacy. The amount of active ingredient that may be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the particular mode of administration. The amount of active ingredient that may be combined with a carrier material to produce a single dosage form will generally be that amount of the compound that produces a therapeutic effect. Generally, on a 100% basis, such amount will be in the range of from about 0.1% to about 99% active ingredient, preferably from about 5% to about 70%, more preferably from about 10% to about 30%.

[0715] In certain embodiments, the formulations of the present invention comprise excipients selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle-forming agents (e.g., bile acids), and polymeric carriers (e.g., polyesters and polyanhydrides); and a compound of the present invention. In certain embodiments, the foregoing formulations facilitate the oral bioavailability of the compound of the present invention.

[0716] Methods of preparing these formulations or compositions include the step of associating a compound of the present invention with a carrier and optionally one or more accessory ingredients. Generally, the formulations are prepared by uniformly and intimately associating a compound of the present invention with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product.

[0717] Formulations of the present invention suitable for oral administration may be presented as capsules, cachets, pills, tablets, lozenges (using a flavoring base, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil emulsion, or as an elixir or syrup, or as a pastille (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and / or as a mouthwash, etc., each containing a predetermined amount of a compound of the present invention as an active ingredient. The compounds of the present invention may also be administered as boluses, electuaries, or pastes.

[0718] In the solid dosage forms of the present invention for oral administration (e.g., capsules, tablets, pills, troches, powders, granules, lozenges, etc.), the active ingredient is mixed with one or more pharmaceutically acceptable carriers (such as sodium citrate or calcium phosphate dibasic) and / or any of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants, such as glycerol; (4) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution blockers, such as paraffin wax; (6) absorption promoters, such as quaternary ammonium compounds, and surfactants, such as poloxamer and sodium lauryl sulfate; (7) wetting agents, such as cetyl alcohol, glyceryl monostearate, and nonionic surfactants; (8) absorbents, such as kaolin and bentonite; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid, and their mixtures; (10) coloring agents; and (11) controlled release agents, such as crospovidone or ethyl cellulose. In the case of capsules, tablets, and pills, the pharmaceutical composition may also contain buffering agents. Solid compositions of a similar type can also be employed as fillers in soft and hard gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0719] Tablets can be made by compressing or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactants, or dispersing agents. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0720] Tablets and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills, and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. The dosage forms may also be formulated, for example, with different proportions of hydroxypropylmethylcellulose to provide slow or controlled release of the active ingredient therein, thus providing the desired release pattern, other polymeric matrices, liposomes, and / or microspheres. The dosage forms may be formulated for rapid release, for example, by lyophilization. The dosage forms may be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating a sterilizing agent in the form of a sterile solid composition, which may be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may have a composition that releases one or more active ingredients in a delayed manner, only in or preferentially in a particular part of the gastrointestinal tract. Examples of embedding compositions that may be used include polymeric substances and waxes. The active ingredient may also be in the form of microcapsules, optionally with one or more of the above excipients where appropriate.

[0721] Liquid dosage forms for oral administration of the compounds of the present invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage forms may also contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifying agents, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters, and mixtures thereof.

[0722] In addition to the inert diluent, the oral compositions may also contain adjuvants, such as wetting agents, emulsifying agents, and suspending agents, sweetening agents, flavoring agents, coloring agents, perfuming agents, and preservatives.

[0723] In addition to the active compound, the suspension may also contain suspending agents, such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar, and tragacanth, and mixtures thereof.

[0724] Preparations of the pharmaceutical compositions of the present invention for rectal or vaginal administration may be presented in the form of suppositories, which may be prepared by mixing one or more compounds of the present invention with one or more suitable non-irritating excipients or carriers, including, for example, cocoa butter, polyethylene glycol, suppository wax, or salicylates, and which are solid at room temperature but liquid at body temperature, and will thus melt in the rectal or vaginal cavity and release the active compound.

[0725] The pharmaceutical formulations of the present invention suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing suitable carriers known in the art.

[0726] Dosage forms for topical or transdermal administration of the compounds of the present invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compounds can be mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers or propellants as may be required.

[0727] In addition to the active compounds of the present invention, ointments, pastes, creams and gels may also contain excipients such as animal and vegetable fats, oils, waxes, paraffin wax, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide or mixtures thereof.

[0728] In addition to the compounds of the present invention, powders and sprays may also contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances. Additionally, sprays may contain conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0729] Transdermal patches have the additional advantage of providing a controlled delivery of the compounds of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the compound in a suitable medium. Penetration enhancers can also be used to increase the flux of the compound through the skin. The rate of such flux can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0730] Ophthalmic preparations, eye ointments, powders, solutions, etc. are also contemplated within the scope of the present invention.

[0731] The pharmaceutical compositions of the present invention suitable for parenteral administration comprise a combination of one or more compounds of the present invention with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions or sterile powders which can be reconstituted into sterile injectable solutions or dispersions immediately before use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostatic agents, solutes rendering the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0732] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate). Appropriate fluidity can be maintained, for example, by using coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by using surfactants.

[0733] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms on the subject compounds may be ensured by including various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, etc. It may also be necessary to include isotonic agents such as sugars, sodium chloride, etc. in the compositions. In addition, the absorption of injectable pharmaceutical forms may be extended by including absorption delaying agents such as aluminum monostearate and gelatin.

[0734] In some cases, in order to prolong the action of a drug, it is necessary to slow the absorption of a drug administered subcutaneously or intramuscularly. This can be achieved by using a liquid suspension of a poorly water-soluble crystalline or amorphous material. The rate of absorption of the drug then depends on its rate of dissolution which may depend on crystal size and crystalline form. Alternatively, delayed absorption of parenterally administered pharmaceutical forms is achieved by dissolving or suspending the drug in an oily vehicle.

[0735] Injectable depot forms are made by forming a microcapsule matrix of the subject compound in a biodegradable polymer such as poly (lactide-co-glycolide). The rate of drug release can be controlled depending on the ratio of the drug to the polymer and the nature of the particular polymer employed. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable preparations are also prepared by entrapping the drug in liposomes or microemulsions compatible with body tissues.

[0736] When the compounds of the present invention are administered to humans and animals as pharmaceuticals, the compounds can be administered per se or as a pharmaceutical composition containing, for example, from 0.1% to 99% (more preferably from 10% to 30%) of the active ingredient in combination with a pharmaceutically acceptable carrier.

[0737] The formulations of the present invention can be administered orally, parenterally, topically, or rectally. Of course, the formulations are administered in a form suitable for each route of administration. By way of example, the formulations are administered in the form of tablets or capsules; administered by injection, inhalation, eye wash, ointment, suppository, etc.; administered by injection, infusion, or inhalation; topically administered by lotion or ointment; and rectally administered by suppository. Oral administration is preferred.

[0738] As used herein, the phrases "parenteral administration" and "parenterally administering" mean modes of administration other than enteral and topical administration, usually by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratracheal, subcutaneous, subepidermal, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.

[0739] As used herein, the phrases "systemic administration", "systemically administering", "peripheral administration", and "peripherally administering" mean administering a compound, drug, or other material in a manner other than directly to the central nervous system such that it enters the patient's system and thereby undergoes metabolism and other similar processes, e.g., subcutaneous administration.

[0740] These compounds can be administered to humans and other animals by any suitable route of administration for therapy, including orally, nasally (e.g., by spray), rectally, intravaginally, parenterally, intracisternally, and topically (e.g., by powder, ointment, or drops), including buccally and sublingually.

[0741] Regardless of the route of administration selected, the compounds of the invention and / or the pharmaceutical compositions of the invention, which can be used in a suitable hydrated form, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art.

[0742] The actual dosage level of the active ingredient in the pharmaceutical compositions of the invention may vary so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, and that is non-toxic to the patient.

[0743] The selected dosage level will depend on a variety of factors, including the activity of the particular compound or its ester, salt, or amide employed in the invention, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds, and / or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health, and prior medical history of the patient being treated, and like factors well known in the medical arts.

[0744] A general physician or veterinarian in the art can readily determine and prescribe the effective amount of the required pharmaceutical composition. For example, the physician or veterinarian can start with a dose of the compound of the invention employed in the pharmaceutical composition at a level lower than that required to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved.

[0745] Generally, the suitable daily dose of the compounds of the invention will be the amount of the lowest dose of the compound that is effective to produce a therapeutic effect. Such effective dose will generally depend on the factors described above. The compounds are preferably administered at about 0.01 mg / kg to about 200 mg / kg, more preferably at about 0.1 mg / kg to about 100 mg / kg, even more preferably at about 0.5 mg / kg to about 50 mg / kg. When the compounds described herein are co-administered with another agent (e.g., as a sensitizer), the effective amount may be lower than the amount when the agent is used alone.

[0746] When necessary, the effective daily dose of the active compound can be administered separately as two, three, four, five, six or more sub-doses at appropriate time intervals throughout the day, optionally in unit dosage forms. Preferably, the administration is once a day.

[0747] The present invention further provides a unit dosage form (such as a tablet or a capsule) containing a therapeutically effective amount of the heterobifunctional substituted phenylpyrimidinone or related compounds described herein for treating the medical conditions described herein.

[0748] IV. Medical Kit

[0749] Another aspect of the present invention is a kit containing (i) a compound described herein, such as a compound of formula I, and (ii) instructions for use, such as for treating cancer.

[0750] V. Enumerated Embodiments

[0751] Another aspect of the present invention provides the following enumerated embodiments:

[0752] Embodiment 1. A compound represented by formula I:

[0753]

[0754] or a pharmaceutically acceptable salt thereof; wherein:

[0755] R 1 is a phenyl group substituted with cyano, halogen and m occurrences of R 4 substituents;

[0756] R 2 and R 3 are independently hydrogen or C 1-4 alkyl;

[0757] R 4 is C 1-4 alkyl;

[0758] R 5 independently represents C 1-4 alkyl or halogen at each occurrence;

[0759] A 1 is a pyridazinylene, pyrimidinylene, pyrazinylene, pyridinylene or phenylene group, each of which is substituted with n occurrences of R 5 substituents;

[0760] L is a linker; and

[0761] A 2 is one of the following:

[0762]

[0763] R 1A is C 1-4 alkyl or C 3-4 cycloalkyl;

[0764] R 2A independently represents C 1-4 alkyl or C 3-4 cycloalkyl;

[0765] R 3A is phenyl substituted by 1, 2 or 3 substituents independently selected from halo, C1-C4 alkyl or C1-C4 haloalkyl;

[0766] R 4A is -(C 1-6 alkylene)-C(O)N(R 5A )(R 6A ), -(C 1-6 alkylene)-N(R 5A )C(O)R 7A ), -(C 1-6 alkylene)-CO2R 7A ), -(C 1-6 alkylene)-OC(O)R 7A or -(C 0-6 alkylene)-(5-6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur);

[0767] R 5A and R 6A are independently hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl; or R 5A and R 6A together with the nitrogen atom to which they are attached form a 3-7-membered ring containing 1 nitrogen atom;

[0768] R 7A is C 1-6 alkyl, -(C 1-6 alkylene)-(C 3-6 cycloalkyl) or C 3-6 cycloalkyl; and

[0769] m, n and p are independently 0, 1 or 2.

[0770] Embodiment 2. The compound according to Embodiment 1, wherein m is 0.

[0771] Embodiment 3. The compound according to Embodiment 1, wherein R 1 is

[0772] Embodiment 4. A compound as described in any one of Embodiments 1-3, wherein R 2 is hydrogen.

[0773] Embodiment 5. A compound as described in any one of Embodiments 1-4, wherein R 3 is hydrogen.

[0774] Embodiment 6. A compound as described in any one of Embodiments 1-5, wherein the compound is a compound of Formula I.

[0775] Embodiment 7. A compound as described in any one of Embodiments 1-5, wherein the compound is a compound of Formula Ia or Formula Ib or a pharmaceutically acceptable salt thereof:

[0776]

[0777] Embodiment 8. A compound as described in any one of Embodiments 1-5, wherein the compound is a compound of Formula Ic or a pharmaceutically acceptable salt thereof:

[0778]

[0779] Embodiment 9. A compound as described in any one of Embodiments 1-5, wherein the compound is a compound of Formula Id or a pharmaceutically acceptable salt thereof:

[0780]

[0781] Embodiment 10. A compound as described in any one of Embodiments 1-9, wherein A 1 is a pyridazinyl group substituted by n occurrences of R 5 substituents.

[0782] Embodiment 11. A compound as described in any one of Embodiments 1-9, wherein A 1 is

[0783] Embodiment 12. A compound as described in any one of Embodiments 1-9, wherein A 1 is a pyrimidinyl group substituted by n occurrences of R 5 substituents.

[0784] Embodiment 13. A compound as described in any one of Embodiments 1-9, wherein A 1 is where * is the point of attachment to L.

[0785] Embodiment 14. A compound as described in any one of Embodiments 1-9, wherein A 1 is Among them, ** is the connection point with L.

[0786] Embodiment 15. The compound according to any one of Embodiments 1-9, wherein A 1 is a pyridazinyl group substituted by R 5 appearing n times.

[0787] Embodiment 16. The compound according to any one of Embodiments 1-9, wherein A 1 is

[0788] Embodiment 17. The compound according to any one of Embodiments 1-9, wherein A 1 is a pyridinyl group substituted by R 5 appearing n times.

[0789] Embodiment 18. The compound according to any one of Embodiments 1-9, wherein A 1 is Among them, ** is the connection point with L.

[0790] Embodiment 19. The compound according to any one of Embodiments 1-9, wherein A 1 is a phenylene group substituted by R 5 appearing n times.

[0791] Embodiment 20. The compound according to any one of Embodiments 1-9, wherein A 1 is

[0792] Embodiment 21. The compound according to any one of Embodiments 1-10, 12, 15, 17 or 19, wherein n is 0.

[0793] Embodiment 22. The compound according to any one of Embodiments 1-21, wherein A 2 is

[0794] Embodiment 23. The compound according to any one of Embodiments 1-22, wherein R 3A is a phenyl group substituted by a halogen group.

[0795] Embodiment 24. The compound according to any one of Embodiments 1-21, wherein A 2 is

[0796] Embodiment 25. The compound according to any one of Embodiments 1-21 or 24, wherein R 4A is -(C 1-6 alkylene)-C(O)N(R 5A )(R6A )。

[0797] Embodiment 26. A compound according to any one of embodiments 1-21 or 24, wherein R 4A is -(C 1-6 alkylene)-CO2R 7A 。

[0798] Embodiment 27. A compound according to any one of embodiments 1-26, wherein R 1A is C 1-4 alkyl.

[0799] Embodiment 28. A compound according to any one of embodiments 1-26, wherein R 1A is methyl.

[0800] Embodiment 29. A compound according to any one of embodiments 1-28, wherein R 2A is C 1-4 alkyl.

[0801] Embodiment 30. A compound according to any one of embodiments 1-28, wherein R 2A is methyl.

[0802] Embodiment 31. A compound according to any one of embodiments 1-30, wherein p is 2.

[0803] Embodiment 32. A compound according to any one of embodiments 1-21, wherein A 2 is

[0804] Embodiment 33. A compound according to any one of embodiments 1-21, wherein A 2 is

[0805] Embodiment 34. A compound according to any one of embodiments 1-21, wherein A 2 is

[0806] Embodiment 35. A compound according to any one of embodiments 1-34, wherein L is a divalent, saturated or unsaturated, straight-chain or branched-chain C 1-60 hydrocarbon chain, wherein 0-20 methylene units of the hydrocarbon are independently replaced by: -O-, -S-, -N(H)-, -N(C 1-6 alkyl)-, -OC(O)-, -C(O)O-, -S(O)-, -S(O)2-, -N(H)S(O)2-, -N(C 1-6 alkyl)S(O)2-, -S(O)2N(H)-, -S(O)2N(C1-6 -alkyl)-, -N(H)C(O)-, -N(C 1-6 alkyl)C(O)-, -C(O)N(H)-, -C(O)N(C 1-6 alkyl)-, -OC(O)N(H)-, -OC(O)N(C 1-6 alkyl)-, -N(H)C(O)O-, -N(C 1-6 alkyl)C(O)O-, an optionally substituted 3-10 membered carbocyclic group, or an optionally substituted 3-10 membered heterocyclic group containing 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0807] Embodiment 36. A compound according to any one of Embodiments 1-34, wherein L is a divalent, saturated, straight or branched chain C 3-30 hydrocarbon chain, wherein 0-15 methylene units of the hydrocarbon are independently replaced by: -O-, -N(H)-, -N(C 1-6 alkyl)-, -OC(O)-, -C(O)O-, -N(H)C(O)-, -N(C 1-6 alkyl)C(O)-, -C(O)N(H)-, -C(O)N(C 1-6 alkyl)-, a 3-10 membered carbocyclic group, or a 3-10 membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0808] Embodiment 37. A compound according to any one of Embodiments 1-34, wherein L is a divalent, saturated, straight or branched chain C 3-30 hydrocarbon chain, wherein 0-15 methylene units of the hydrocarbon are independently replaced by: -O-, -N(H)-, -N(C 1-6 alkyl)-, -OC(O)-, -C(O)O-, -N(H)C(O)-, -N(C 1-6 alkyl)C(O)-, -C(O)N(H)- or -C(O)N(C 1-6 alkyl)-.

[0809] Embodiment 38. A compound according to any one of Embodiments 1-34, wherein L is a divalent, saturated or unsaturated, straight or branched chain C 5-40 hydrocarbon chain, wherein 1-20 methylene units of the hydrocarbon are independently replaced by: -O-, -N(H)-, -N(C 1-6 alkyl)-, -N(H)C(O)-, -N(C 1-6 alkyl)C(O)-, -C(O)N(H)-, -C(O)N(C 1-6alkyl)-, optionally substituted 3- to 10-membered carbocyclic group, or optionally substituted 3- to 10-membered heterocyclic group containing 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0810] Embodiment 39. The compound according to any one of Embodiments 1-34, wherein L is -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(OCH2CH2) 1-15 -O-***, where *** is the point of attachment to A 2 of the connection.

[0811] Embodiment 40. The compound according to any one of Embodiments 1-34, wherein L is -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(OCH2CH2) 1-5 -O-***, where *** is the point of attachment to A 2 of the connection.

[0812] Embodiment 41. The compound according to any one of Embodiments 1-34, wherein L is -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(OCH2CH2) 6-10 -O-***, where *** is the point of attachment to A 2 of the connection.

[0813] Embodiment 42. The compound according to any one of Embodiments 1-34, wherein L is -piperidinyl-(OCH2CH2) 1-15 -O-***, where *** is the point of attachment to A 2 of the connection.

[0814] Embodiment 43. The compound according to any one of Embodiments 1-34, wherein L is where *** is the point of attachment to A 2 of the connection.

[0815] Embodiment 44. The compound according to any one of Embodiments 1-34, wherein L is where *** is the point of attachment to A 2 of the connection.

[0816] Embodiment 45. The compound according to any one of Embodiments 1-34, wherein L is where *** is the point of attachment to A 2 of the connection.

[0817] Embodiment 46. The compound according to any one of Embodiments 1-34, wherein L is -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(OCH2CH2) 1-15-N(H)C(O)-C 1-10 alkylene-***, -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(OCH2CH2) 1-15 -N(C 1-4 alkyl)C(O)-C 1-10 alkylene-***, -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(OCH2CH2) 1-15 -C(O)N(H)-C 1-10 alkylene-*** or -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(OCH2CH2) 1-15 -C(O)N(C 1-4 alkyl)-C 1-10 alkylene-***, where *** is the point of attachment to A 2 of the attachment point.

[0818] Embodiment 47. A compound according to any one of Embodiments 1-34, wherein L is -piperidinyl-(OCH2CH2) 1-5 -N(H)C(O)-C 1-5 alkylene-***, -piperidinyl-(OCH2CH2) 1-5 -N(C 1-4 alkyl)C(O)-C 1-5 alkylene-***, -piperidinyl-(OCH2CH2) 1-5 -C(O)N(H)-C 1-5 alkylene-*** or -piperidinyl-(OCH2CH2) 1-5 -C(O)N(C 1-4 alkyl)-C 1-5 alkylene-***, where *** is the point of attachment to A 2 of the attachment point.

[0819] Embodiment 48. A compound according to any one of Embodiments 1-34, wherein L is -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(OCH2CH2) 1-10 -***, -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-10 alkylene)-O-*** or -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-C 1-10 alkylene, where *** is the point of attachment to A 2 of the attachment point.

[0820] Embodiment 49. A compound according to any one of Embodiments 1-34, wherein L is -piperidinyl-(OCH2CH2)1-5 -***, -piperidinyl-(C 0-5 alkylene)-O-*** or -piperidinyl-(C 1-5 alkylene)-***, where *** is the point of attachment to A 2 .

[0821] Embodiment 50. A compound according to any one of Embodiments 1-34, wherein L is -(a 3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-X 1 -***, where *** is the point of attachment to A 2 and X 1 is (i) C 1-10 alkylene, wherein 1 or 2 methylene groups are optionally replaced by -O-, -N(H)- or -N(C 1-4 alkyl)-, (ii) a 3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen, or (iii) -(a 3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(C 1-10 alkylene)-.

[0822] Embodiment 51. A compound according to any one of Embodiments 1-34, wherein L is -(piperidinyl)-X 1 -***, where *** is the point of attachment to A 2 and X 1 is (i) C 1-5 alkylene, wherein 1 or 2 methylene groups are optionally replaced by -O-, -N(H)- or -N(C 1-4 alkyl)-, (ii) a 3- to 4-membered monocyclic saturated heterocycle containing 1 heteroatom selected from nitrogen, or (iii) -(a 3- to 4-membered monocyclic saturated heterocycle containing 1 heteroatom selected from nitrogen)-(C 1-5 alkylene)-.

[0823] Embodiment 52. A compound according to any one of Embodiments 1-34, wherein L is where *** is the point of attachment to A 2 and X 1 is (i) C 1-10 alkylene, wherein 1 or 2 methylene groups are optionally replaced by -O-, -N(H)- or -N(C 1-4 alkyl)-, (ii) a 3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen, or (iii) -(a 3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(C 1-10 alkylene)-.

[0824] Compound according to any one of embodiments 1 - 34, wherein L is -(piperazinyl)-X 1 -***, where *** is the point of attachment to A 2 and X 1 is (i) C 1-5 alkylene, where 1 or 2 methylene groups are optionally replaced by -O-, (ii) a 3 - 4 membered monocyclic saturated heterocycle containing 1 heteroatom selected from nitrogen, or (iii) -(a 3 - 4 membered monocyclic saturated heterocycle containing 1 heteroatom selected from nitrogen)-(C 1-5 alkylene)-.

[0825] Embodiment 54. A compound according to any one of embodiments 1 - 34, wherein L is where *** is the point of attachment to A 2 and X 1 is (i) C 1-10 alkylene, where 1 or 2 methylene groups are optionally replaced by -O-, (ii) a 3 - 7 membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen, or (iii) -(a 3 - 7 membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(C 1-10 alkylene)-.

[0826] Embodiment 55. A compound according to any one of embodiments 1 - 34, wherein L is -(a 3 - 7 membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-X 2 -(C 1-10 alkylene)-***, where *** is the point of attachment to A 2 and X 2 is -O-, -N(H)- or -N(C 1-6 alkyl)-.

[0827] Embodiment 56. A compound according to any one of embodiments 1 - 34, wherein L is -(piperidinyl)-X 2 -(C 1-10 alkylene)-***, where *** is the point of attachment to A 2 and X 2 is -O-, -N(H)- or -N(C 1-6 alkyl)-.

[0828] Embodiment 57. A compound according to any one of embodiments 1 - 34, wherein L is -(piperidinyl)-X 2 -(a 3 - 7 membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-***, where *** is the point of attachment to A 2 and X 2is -O-, -N(H)- or -N(C 1-6 alkyl)-.

[0829] Embodiment 58. The compound according to any one of Embodiments 1-34, wherein L is where *** is the point of attachment to A 2 and X 2 is -O-, -N(H)- or -N(C 1-6 alkyl)-.

[0830] Embodiment 59. The compound according to any one of Embodiments 1-34, wherein L is where *** is the point of attachment to A 2 and X 2 is -O-, -N(H)- or -N(C 1-6 alkyl)-.

[0831] Embodiment 60. The compound according to any one of Embodiments 55-59, wherein X 2 is -O-.

[0832] Embodiment 61. The compound according to any one of Embodiments 1-34, wherein L is -(a 3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-X 1 -***, where *** is the point of attachment to A 2 and X 1 is -(OCH2CH2) 1-10 , where 1 CH2 group is optionally replaced by -C(H)(C 3-6 cycloalkyl)-.

[0833] Embodiment 62. The compound according to any one of Embodiments 1-34, wherein L is a 7- to 11-membered spiro or fused bicyclic saturated heterocycle containing 1, 2 or 3 heteroatoms selected from nitrogen and oxygen.

[0834] Embodiment 63. The compound according to any one of Embodiments 1-34, wherein L is a 7- to 8-membered spiro or fused bicyclic saturated heterocycle containing 2 heteroatoms selected from nitrogen.

[0835] Embodiment 64. The compound according to any one of Embodiments 1-34, wherein L is -(a 3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-X 3 -(a 3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-, where X 3 is C 1-10 alkylene, -O-, -N(H)-, -N(C 1-4 alkyl)- or a bond.

[0836] Embodiment 65. The compound according to any one of Embodiments 1-34, wherein L is -(piperidinyl)-(C 1-5 alkylene)-(piperazinyl)-***, where *** is the point of attachment to A 2 .

[0837] Embodiment 66. The compound according to any one of Embodiments 1-34, wherein L is -(piperazinyl)-(azetidinyl)-*** or (azetidinyl)-(piperazinyl)-***, where *** is the point of attachment to A 2 .

[0838] Embodiment 67. The compound according to any one of Embodiments 1-34, wherein L is -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-X 3 -(C 3-6 subcycloalkyl)-O-***, -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-X 3 -(C 3-6 subcycloalkyl)-N(H)-*** or -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-X 3 -(C 3-6 subcycloalkyl)-N(C 1-4 alkyl)-***, where *** is the point of attachment to A 2 , and X 3 is C 1-10 alkylene, -O-, -N(H)-, -N(C 1-4 alkyl)- or a bond.

[0839] Embodiment 68. The compound according to any one of Embodiments 1-34, wherein L is -(piperidinyl)-X 3 -(C 3-6 subcycloalkyl)-O-***, -(piperidinyl)-X 3 -(C 3-6 subcycloalkyl)-N(H)-*** or -(piperidinyl)-X 3 -(C 3-6 subcycloalkyl)-***, where *** is the point of attachment to A 2 , and X 3 is C 1-10 alkylene, -O-, -N(H)-, -N(C 1-4 alkyl)- or a bond.

[0840] Embodiment 69. The compound according to any one of Embodiments 1-34, wherein L has the formula -(C 0-12(Alkylene)-(optionally substituted 3-40-membered heteroalkylene)-(C 0-12 alkylene)-.

[0841] Embodiment 70. A compound according to any one of Embodiments 1-34, wherein L is one of the following:

[0842]

[0843]

[0844] where *** is the point of attachment to A 2 of.

[0845] Embodiment 71. A compound according to any one of Embodiments 1-34, wherein L is one of the following:

[0846]

[0847] where *** is the point of attachment to A 2 of.

[0848] Examples

[0849] The invention now generally described will be more readily understood by reference to the following examples, which are included for the purpose of illustrating certain aspects and embodiments of the invention only and are not intended to limit the invention.

[0850] General Methods

[0851] All reactions were carried out under a dry nitrogen or argon atmosphere. Glassware was dried before use. Unless otherwise indicated, common reagents or materials were obtained from commercial sources and used without further purification. Anhydrous N,N-diisopropylethylamine (DIPEA) was obtained by distillation over potassium hydroxide. Tetrahydrofuran (THF), dichloromethane (CH2Cl2), and dimethylformamide (DMF) were dried by a PureSolv TM solvent drying system. PTLC refers to preparative thin-layer chromatography separation. Abbreviations: HFIP (hexafluoroisopropanol), HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid). Flash column chromatography was performed using silica gel 60 (230-400 mesh). Analytical thin-layer chromatography (TLC) was carried out on Merck silica gel plates with QF-254 indicator and visualized by UV or KMnO4.

[0852] At room temperature on an Agilent DD2 500 (500 MHz 1 H; 125 MHz 13 C) or an Agilent DD2 600 (600 MHz 1 H; 150 MHz13 C) or Agilent DD2 400 (400 MHz 1 H; 100 MHz 13 C) spectra were recorded on 1 H and 13 C NMR spectra. Chemical shifts were reported in ppm relative to residual CDCl3 (δ 7.26 ppm 1 H; δ 77.0 ppm 13 C), CD3OD (δ 3.31 ppm 1 H; δ 49.00 ppm 13 C) or d6-DMSO (δ 2.50 ppm 1 H; δ 39.52 ppm 13 C). NMR chemical shifts were expressed in ppm relative to the internal solvent peak, and coupling constants were measured in Hz (bs = broad signal). In most cases, only the peaks of the major rotamers were reported.

[0853] Mass spectra were obtained using an Agilent 1100 series LC / MSD spectrometer. Analytical HPLC analysis was performed using gradient conditions (10 - 100% B, flow rate = 1.0 mL / min, 20 min) on a 250×4.6 mm C-18 column or as described in the LC-MS method table.

[0854] Unless otherwise indicated, preparative HPLC was performed using gradient conditions (10 - 100% B, flow rate = 10.0 mL / min, 20 min) on a 250×21.2 mm C-18 column. The eluents used were: solvent A (H2O containing 0.1% TFA) and solvent B (CH3CN containing 0.1% TFA). The final product was usually purified via reverse-phase HPLC, PTLC, or flash column chromatography.

[0855]

[0856]

[0857]

[0858]

[0859]

[0860]

[0861]

[0862]

[0863] The following abbreviations are used in this text: ACN: acetonitrile; Bn: benzyl; Boc: tert-butoxycarbonyl; DCM: dichloromethane; DIEA: diisopropylethylamine; DMAP: 4-dimethylaminopyridine; DMF: dimethylformamide; DMSO: dimethyl sulfoxide; EtOH: ethanol; EA or EtOAc: ethyl acetate; equiv. or eq.: molar equivalent; FA: formic acid; h: hour; HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; HPLC: high performance liquid chromatography; JQ1: 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2,6 trideca-2(6),4,7,10,12-pentaen-9-yl]acetic acid; LCMS or LC-MS: liquid chromatography-mass spectrometry; MeOH: methanol; MS: mass spectrometry; NMP: N-methylpyrrolidone; NMR: nuclear magnetic resonance; PE: petroleum ether; rt: room temperature; TEA: triethylamine; TFA: trifluoroacetic acid; THF: tetrahydrofuran; and Tos or Ts: tosyl.

[0864] Example 1 - Synthesis of N-[4-(3-chloro-4-cyanophenoxy)cyclohexyl]-6-[4-[2-[[2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2,6 trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethoxy]-1-piperidinyl]pyridazine-3-carboxamide (I-1)

[0865]

[0866]

[0867] Step 1: Preparation of tert-butyl 4-[2-(1,3-dioxoisoindolin-2-yl)ethoxy]piperidine-1-carboxylate. A solution of tert-butyl 4-[2-(p-toluenesulfonyloxy)ethoxy]piperidine-1-carboxylate (517 mg, 1.3 mmol, 1.2 eq) and potassium (1,3-dioxoisoindolin-2-yl) (200 mg, 1.1 mmol, 1.0 eq) in DMF (5 mL) was stirred at 50 °C for 12 h. The mixture was partitioned between H2O (50 mL) and ethyl acetate (100 mL). The organic phase was separated, washed with H2O (2 × 50 mL), dried over Na2SO4, filtered and concentrated to give tert-butyl 4-[2-(1,3-dioxoisoindolin-2-yl)ethoxy]piperidine-1-carboxylate as a yellow solid (400 mg, 98% yield).

[0868] Step 2: Preparation of tert-butyl 4-(2-aminoethoxy)piperidine-1-carboxylate. NH2NH2·H2O (5.9 g, 118 mmol, 17 eq) was added to a solution of tert-butyl 4-[2-(1,3-dioxoisoindolin-2-yl)ethoxy]piperidine-1-carboxylate (2.5 g, 6.7 mmol, 1.0 eq) in ethanol (20 mL). The mixture was stirred at 70 °C for 12 h. The residue was purified by preparative HPLC (column: Waters Xbridge 150×25 mm, 5 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 12%-42%, 10 min) to give tert-butyl 4-(2-aminoethoxy)piperidine-1-carboxylate as a white oil (800 mg, 49% yield). 1 1H NMR (400 MHz, CDCl3): δ 1.47 (s, 9H), 1.50 - 1.60 (m, 5H), 1.76 - 1.92 (m, 2H), 2.87 (t, J = 5.20 Hz, 2H), 3.06 - 3.13 (m, 2H), 3.40 - 3.55 (m, 3H), 3.69 - 3.85 (m, 2H).

[0869] Step 3: Preparation of tert-butyl 4-[2-[[2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2,6 trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethoxy]piperidine-1-carboxylate. To tert-butyl 4-(2-aminoethoxy)piperidine-1-carboxylate (100 mg, 409 μmol, 1.0 eq) and 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2,6A solution of [[2E,4E,6E,8E,10E]-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,7]trideca-2(6),4,7,10,12-pentaen-9-yl]acetic acid (164 mg, 409 μmol, 1.0 equiv) in DMF (3 mL) was added with HATU (171 mg, 450 μmol, 1.1 equiv) and diisopropylethylamine (211 mg, 1.64 mmol, 4.0 equiv). The mixture was stirred at 25 °C for 0.5 h and purified by preparative HPLC (column: Waters Xbridge C18 150×50 mm, 10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 40%-70%, 10 min) to give tert-butyl 4-[2-[[2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2,6 trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethoxy]piperidine-1-carboxylate (150 mg, 58% yield) as a white solid.

[0870] Step 4: Preparation of 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2,6 trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[2-(piperidin-4-yloxy)ethyl]acetamide. To a solution of tert-butyl 4-[2-[[2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2,6 trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethoxy]piperidine-1-carboxylate (75 mg, 119 μmol, 1.0 equiv) in DCM (4 mL) was added TFA (1.0 mL). The mixture was stirred at 25 °C for 0.5 h. The residue was used directly for the next step.

[0871] Step 5: Preparation of N-[4-(3-chloro-4-cyanophenoxy)cyclohexyl]-6-[4-[2-[[2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2,6 trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethoxy]-1-piperidinyl]pyridazine-3-carboxamide (I-1). To 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2,6To a solution of 1-tridecyl-2(6),4,7,10,12-pentaen-9-yl]-N-[2-(4-piperidinyloxy)ethyl]acetamide (75 mg, 116 μmol, 1.0 equiv, TFA salt) and 6-chloro-N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]pyridazine-3-carboxamide (45 mg, 116 μmol, 1.0 equiv) in NMP (2 mL) was added K2CO3 (32 mg, 233 μmol, 2.0 equiv). The mixture was stirred at 50°C for 12 h. The residue was purified by preparative HPLC (column: Unisil 3-100C18 Ultra 150×50 mm, 3 μm; mobile phase: [water (FA)-ACN]; B%: 50%-80%, 10 min) to give N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[4-[2-[[2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[83.0.0]) as a white solid. 2,6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethoxy]-1-piperidinyl]pyridazine-3-carboxamide (35 mg, 34% yield). 1 H NMR (400MHz, DMSO-d6): δ1.44-1.56(m,4H),1.60-1.70(m,5H),1.87-1.96(m,4H),2.0 7-2.14(m,2H),3.18-3.32(m,7H),3.39-3.42(m,5H),3.52(t,J=5.69Hz,2H),3.63-3. 66(m,1H),3.80-3.97(m,1H),4.02-4.19(m,2H),4.49-4.61(m,2H),7.12-7.15(m,1H) ,7.33-7.49(m,6H),7.80-7.87(m,2H),8.27(t,J=5.50Hz,1H),8.59(d,J=8.0Hz,1H). LC-MS:MS(ES + ): RT = 2.652 min, m / z = 441.1, 881.2; LC-MS method 25.

[0872] Example 2 -Synthesis of N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[4-[2-[2-[2-[2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2,6]Tridecane-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethoxy]ethoxy]ethoxy]-1-piperidinyl]pyridazine-3-carboxamide (I-2)

[0873]

[0874] To 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2,6 To a solution of 1-tridecyl-2(6),4,7,10,12-pentaen-9-yl]-N-[2-[2-[2-(4-piperidinyloxy)ethoxy]ethoxy]ethyl]acetamide (71 mg, 97 μmol, 1.0 equiv, TFA salt) in NMP (1 mL) was added K2CO3 (40 mg, 292 μmol, 3.0 equiv) and 6-chloro-N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]pyridazine-3-carboxamide (42 mg, 107 μmol, 1.1 equiv). The mixture was stirred at 50° C. for 6 h and concentrated. The residue was purified by preparative HPLC (column: Waters Xbridge 150×25 mm, 5 μm; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 46%-76%, 9 min) to give N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[4-[2-[2-[2-[2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[83.0.0]) as a white solid. 2,6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethoxy]ethoxy]ethoxy]-1-piperidinyl]pyridazine-3-carboxamide (I-12) (37.8 mg, 39% yield). 11H NMR (400 MHz, DMSO-d6): δ 8.46 (d, J = 8.0 Hz, 1H), 8.14 (t, J = 5.6 Hz, 1H), 7.8 (m, 2H), 7.45 (q, J = 8.6 Hz, 4H), 7.27 - 7.38 (m, 2H), 7.13 (m, 1H), 4.48 - 4.59 (m, 2H), 4.00 - 4.11 (m, 2H), 3.80 - 3.92 (m, 1H), 3.52 - 3.72 (m, 9H), 3.46 - 3.51 (m, 2H), 3.35 - 3.44 (m, 2H), 3.24 - 3.33 (m, 3H), 3.18 - 3.21 (m, 1H), 2.59 (s, 3H), 2.40 (s, 3H), 2.06 - 2.15 (m, 2H), 1.91 (d, J = 3.0 Hz, 4H), 1.44 - 1.72 (m, 9H). LC-MS: MS (ES + ): RT = 2.922 min, m / z = 486.0, 971.2; LC-MS method 10.

[0875] Example 3 - Synthesis of N-[4-(3-chloro-4-cyanophenoxy)cyclohexyl]-6-[4-[2-[2-[2-[2-[2-[[2-[7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2,6 trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-1-piperidinyl]pyridazine-3-carboxamide (I-3)

[0876]

[0877] Step 1: Preparation of tert-butyl 4-[2-[2-[2-[2-[2-(1,3-dioxoisoindolin-2-yl)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]piperidine-1-carboxylate. To a solution of tert-butyl 4-[2-[2-[2-[2-[2-(p-toluenesulfonyloxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]piperidine-1-carboxylate (6.10 g, 10.59 mmol, 1.0 equiv) in DMF (120 mL) was added potassium (1+) (1,3-dioxoisoindolin-2-yl) (3.92 g, 21.18 mmol, 2.0 equiv). The mixture was stirred at 50 °C for 12 h. Water (120 mL) was added to the reaction mixture, and the mixture was extracted with EtOAc (100 mL). The combined organic phases were washed with brine (200 mL × 3), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, PE / EA = 5 / 1 to 0 / 1) to give tert-butyl 4-[2-[2-[2-[2-[2-(1,3-dioxoisoindolin-2-yl)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]piperidine-1-carboxylate as a yellow oil (4.83 g, 83% yield).

[0878] Step 2: Preparation of tert-butyl 4-[2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]piperidine-1-carboxylate. To a solution of tert-butyl 4-[2-[2-[2-[2-[2-(1,3-dioxo-3a,7a-dihydroisoindol-2-yl)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]piperidine-1-carboxylate (1.0 g, 1.8 mmol, 1.0 equiv) in EtOH (30 mL) was added N2H4·H2O (924 mg, 18 mmol, 98% purity, 10 equiv). The mixture was stirred at 70 °C for 2 h and concentrated. The residue was purified by preparative HPLC (column: Shim-pack C 18 150×25, 10 μm; mobile phase: [water (FA)-ACN]; B%: 5%-35%, 10 min) to give tert-butyl 4-[2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]piperidine-1-carboxylate (620 mg, 81% yield). 1 1H NMR (400 MHz, CDCl3) δ 8.57 - 8.50 (m, 1H), 3.90 - 3.60 (m, 20H), 3.53 - 3.43 (m, 2H), 3.10 - 3.07 (m, 2H), 2.99 (s, 2H), 1.92 - 1.82 (m, 2H), 1.53 - 1.48 (m, 1H), 1.46 (s, 9H).

[0879] Step 3: Preparation of tert-butyl 4-[2-[2-[2-[2-[2-[[2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2,6 trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]piperidine-1-carboxylate. To a solution of tert-butyl 4-[2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]piperidine-1-carboxylate (100 mg, 237 μmol, 1 equiv), 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2,6 trideca-2(6),4,7,10,12-pentaen-9-yl]acetic acid (95 mg, 237 μmol, 1.0 equiv) in DMF (3 mL) was added DIEA (92 mg, 713 μmol, 3.0 equiv) and HATU (135 mg, 356 μmol, 1.5 equiv). The mixture was stirred at 20 °C for 0.5 h and concentrated. The residue was purified by preparative HPLC (column: Waters Xbridge 150×25 mm, 5 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 46%-76%, 8 min) to give tert-butyl 4-[2-[2-[2-[2-[2-[[2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2,6 trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]piperidine-1-carboxylate (120 mg, 62% yield).

[0880] Step 4: Preparation of 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2,6 trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[2-[2-[2-[2-[2-(4-piperidinyloxy)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]acetamide. To a solution of 4-[2-[2-[2-[2-[2-[[2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2,6tert-Butyl [[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2,6 trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]piperidine-1-carboxylate (120 mg, 149 μmol, 1.0 equiv) was added to a solution of TFA (1 mL) in DCM (2 mL). The mixture was stirred at 25 °C for 0.5 h and concentrated to give 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0

[0881] Step 5: Preparation of N-[4-(3-chloro-4-cyanophenoxy)cyclohexyl]-6-[4-[2-[2-[2-[2-[2-[[2-[7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2,6 trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-1-piperidyl]pyridazine-3-carboxamide (I-3). To a solution of 2-[7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2,6 trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[2-[2-[2-[2-[2-(4-piperidyloxy)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]acetamide (120 mg, 146 μmol, 1.0 equiv) in NMP (2 mL) was added K2CO3 (202 mg, 1.47 mmol, 10 equiv) and 6-chloro-N-[4-(3-chloro-4-cyanophenoxy)cyclohexyl]pyridazine-3-carboxamide (57 mg, 146 μmol, 1.0 equiv). The mixture was stirred at 70 °C for 3 h and concentrated. The residue was purified by preparative HPLC (column: Unisil 3-100C 18 Ultra 150×50 mm, 3 μm; mobile phase: [water (FA)-ACN]; B%: 50%-80%, 5 min) to give N-[4-(3-chloro-4-cyanophenoxy)cyclohexyl]-6-[4-[2-[2-[2-[2-[2-[[2-[7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-1-piperidinyl]pyridazine-3-carboxamide (73 mg, 46% yield). 1 H NMR (400MHz, CDCl3) δ8.12-8.06(m,1H),7.93-7.85(m,1H),7.57(d,J=8.8Hz,1H),7.47-7.32(m,4H),7.22- 7.10(m,1H),7.01(d,J=2.3Hz,1H),6.86(s,1H),4.79-4.68(m,1H),4.40-4.26(m,1H),4.09-4.01(m,3H),3. 99-3.85(m,1H),3.83-3.72(m,2H),3.71-3.65(m,17H),3.60(s,2H),3.56-3.45(m,4H),2.75(s,2H),2.44- 2.41(m,3H),2.26-2.07(m,6H),2.04-1.88(m,3H),1.85-1.78(m,2H),1.68-1.60(m,2H),1.55-1.47(m,2H). LC-MS:MS(ES + ): RT = 2.909 min, m / z = 530.1, 1059.3; LC-MS method 10.

[0882] Example 4 -Synthesis of N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[4-[2-[2-[2-[2-[2-[2-[2-[2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-1-piperidinyl]pyridazine-3-carboxamide (I-4)

[0883]

[0884]

[0885] Step 1: Preparation of 2-[2-[2-[2-[2-[2-(2-benzyloxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate. To a solution of 2-[2-[2-[2-[2-[2-(2-benzyloxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol (19 g, 45.6 mmol, 1 eq.) in DCM (150 mL) at 0 °C was added Et3N (13.8 g, 137 mmol, 3 eq.), DMAP (557 mg, 4.56 mmol, 0.1 eq.) and TosCl (13 g, 68.4 mmol, 1.5 eq.). The mixture was stirred at 20 °C for 12 h. The mixture was partitioned between water (30 mL). The organic phase was separated, washed with ethyl acetate (3 × 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (SiO2, PE / EA 1 / 1 to 1 / 10) to give 2-[2-[2-[2-[2-[2-(2-benzyloxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate as a yellow oil (20.7 g, 79% yield). 1 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 8.4 Hz, 2H), 7.29 - 7.18 (m, 7H), 4.49 (s, 2H), 4.10 - 4.06 (m, 2H), 3.64 - 3.50 (m, 26H), 2.37 (s, 3H).

[0886] Step 2: Preparation of tert-butyl 4-[2-[2-[2-[2-[2-[2-(2-benzyloxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]piperidine-1-carboxylate. To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (3.77 g, 18.7 mmol, 1 equiv) in THF (100 mL) at 0 °C was added NaH (900 mg, 22.5 mmol, 60% purity, 1.2 equiv). The mixture was stirred at 20 °C for 0.5 h and 2-[2-[2-[2-[2-[2-(2-benzyloxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (10.7 g, 18.7 mmol, 1 equiv) was added at 0 °C. The mixture was stirred at 20 °C for 12 h. The reaction mixture was poured into water (60 mL) and extracted with ethyl acetate (3 × 100 mL). The organic phase was dried over Na2SO4 and concentrated. The residue was purified by column chromatography (SiO2, PE / EA 1 / 0 to 0 / 1) to give tert-butyl 4-[2-[2-[2-[2-[2-[2-(2-benzyloxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]piperidine-1-carboxylate as a yellow oil (9 g, 80% yield). 1 H NMR (400 MHz, CDCl3) δ 7.34 (d, J = 4.4 Hz, 5H), 4.57 (s, 2H), 3.70 - 3.63 (m, 33H), 2.05 (s, 2H), 1.58 - 1.49 (m, 2H), 1.46 (s, 9H).

[0887] Step 3: Preparation of tert-butyl 4-[2-[2-[2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]piperidine-1-carboxylate. To a solution of tert-butyl 4-[2-[2-[2-[2-[2-[2-(2-benzyloxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]piperidine-1-carboxylate (9 g, 15 mmol, 1 equiv) in MeOH (100 mL) was added Pd(OH)2 (1 g, 713 μmol, 10% purity). The mixture was stirred at 30 °C under H2 (50 Psi) for 12 h. The mixture was concentrated under reduced pressure to give tert-butyl 4-[2-[2-[2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]piperidine-1-carboxylate as a yellow oil (7.56 g, 99% yield). 1 H NMR (400 MHz, CDCl3) δ 3.68 - 3.64 (m, 33H), 1.89 - 1.78 (m, 2H), 1.59 - 1.49 (m, 2H), 1.46 (s, 9H).

[0888] Step 4: Preparation of tert-butyl 4-[2-[2-[2-[2-[2-[2-[2-(p-toluenesulfonyloxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]piperidine-1-carboxylate. TosCl (281 mg, 1.47 mmol, 1.5 eq) and TEA (298 mg, 2.94 mmol, 3 eq) were added to a solution of tert-butyl 4-[2-[2-[2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]piperidine-1-carboxylate (500 mg, 981 μmol, 1 eq) in DCM (2 mL) at 0 °C. The mixture was stirred at 20 °C for 12 h and concentrated. The residue was purified by column chromatography (PE / EA 10 / 1 to 1 / 2) to afford tert-butyl 4-[2-[2-[2-[2-[2-[2-[2-(p-toluenesulfonyloxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]piperidine-1-carboxylate (650 mg, 100% yield) as a yellow oil.

[0889] Step 5: Preparation of tert-butyl 4-[2-[2-[2-[2-[2-[2-[2-(1,3-dioxoisoindolin-2-yl)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]piperidine-1-carboxylate. Potassium (1,3-dioxoisoindolin-2-yl) (349 mg, 1.88 mmol, 1 eq) was added to a solution of tert-butyl 4-[2-[2-[2-[2-[2-[2-[2-(p-toluenesulfonyloxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]piperidine-1-carboxylate (1.5 g, 2.26 mmol, 1.2 eq) in DMF (10 mL). The mixture was stirred at 50 °C for 12 h. The mixture was poured into water (20 mL) and extracted with ethyl acetate (3 × 30 mL). The organic phase was dried over Na2SO4 and concentrated. The residue was purified by column chromatography (SiO2, PE / EA 1 / 0 to 0 / 1) to afford tert-butyl 4-[2-[2-[2-[2-[2-[2-[2-(1,3-dioxoisoindolin-2-yl)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]piperidine-1-carboxylate (1 g, 87% yield) as a yellow oil.

[0890] Step 6: Preparation of tert-butyl 4-[2-[2-[2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]piperidine-1-carboxylate. To a solution of tert-butyl 4-[2-[2-[2-[2-[2-[2-[2-(1,3-dioxoisoindolin-2-yl)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]piperidine-1-carboxylate (1.05 g, 1.64 mmol, 1 equiv) in EtOH (100 mL) was added NH2NH2 . H2O (1.36 g, 27.2 mmol, 16.5 equiv). The mixture was stirred at 80 °C for 12 h and concentrated. The residue was purified by preparative HPLC (column: Waters Xbridge 150×25 mm, 5 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 10%-40%, 10 min) to give tert-butyl 4-[2-[2-[2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]piperidine-1-carboxylate as a yellow oil (400 mg, 48% yield).

[0891] Step 7: Preparation of tert-butyl 4-[2-[2-[2-[2-[2-[2-[2-[[2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]piperidine-1-carboxylate. To a solution of tert-butyl 4-[2-[2-[2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]piperidine-1-carboxylate (100 mg, 197 μmol, 1 equiv) in DMF (2 mL) was added 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetic acid (79 mg, 153 μmol, 7.79e-1 equiv, TFA salt), HATU (90 mg, 236 μmol, 1.2 equiv), and DIEA (127 mg, 983 μmol, 5 equiv). The mixture was stirred at 25 °C for 0.5 h and concentrated. The residue was purified by preparative HPLC (column: Waters Xbridge 150×25 mm, 5 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 49%-79%, 8 min) to give tert-butyl 4-[2-[2-[2-[2-[2-[2-[2-[[2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]piperidine-1-carboxylate as a yellow oil (170 mg, 97% yield).

[0892] Step 8: Preparation of 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[2-[2-[2-[2-[2-[2-[2-(4-piperidinyloxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]acetamide. To a solution of tert-butyl 4-[2-[2-[2-[2-[2-[2-[2-[[2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]piperidine-1-carboxylate (80 mg, 90 μmol, 1 equiv) in DCM (1 mL) was added TFA (0.5 mL). The mixture was stirred at 25 °C for 0.5 h and concentrated to afford 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[2-[2-[2-[2-[2-[2-[2-(4-piperidinyloxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]acetamide (80 mg, 98% yield, TFA salt) as a yellow oil.

[0893] Step 9: Preparation of N-[4-(3-chloro-4-cyanophenoxy)cyclohexyl]-6-[4-[2-[2-[2-[2-[2-[2-[2-[[2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-1-piperidinyl]pyridazine-3-carboxamide (I-4). To a solution of 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[2-[2-[2-[2-[2-[2-[2-(4-piperidinyloxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]acetamide (80 mg, 88 μmol, 1 equiv., TFA salt) in NMP (1 mL) was added K2CO3 (122 mg, 884 μmol, 10 equiv.) and 6-chloro-N-[4-(3-chloro-4-cyanophenoxy)cyclohexyl]pyridazine-3-carboxamide (35 mg, 88 μmol, 1 equiv.). The mixture was stirred at 70 °C for 12 h and concentrated. The residue was purified by preparative HPLC (column: Unisil 3-100C 18 Ultra 150×50 mm, 3 μm; mobile phase: [water (FA)-ACN]; B%: 45%-75%, 10 min) to give N-[4-(3-chloro-4-cyanophenoxy)cyclohexyl]-6-[4-[2-[2-[2-[2-[2-[2-[2-[[2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-1-piperidinyl]pyridazine-3-carboxamide (I-14) (29 mg, 26% yield) as a white solid. 11H NMR (400 MHz, methanol-d4) δ 7.90 (d, J = 9.6 Hz, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.51 - 7.40 (m, 4H), 7.30 (d, J = 9.6 Hz, 1H), 7.21 (d, J = 2.4 Hz, 1H), 7.06 (dd, J = 2.4, 8.8 Hz, 1H), 4.66 (dd, J = 5.2, 9.0 Hz, 1H), 4.56 - 4.49 (m, 1H), 4.10 (m, J = 3.6, 6.8, 13.2 Hz, 2H), 4.03 - 3.95 (m, 1H), 3.68 - 3.43 (m, 32H), 2.71 (s, 3H), 2.46 (s, 3H), 2.23 - 2.08 (m, 4H), 2.04 - 1.96 (m, 2H), 1.74 - 1.59 (m, 10H). LC-MS: MS (ES + ): RT = 2.928 min, m / z = 573.2, 1145.3; LC-MS method 10.

[0894] Example 5 - Synthesis of additional compounds

[0895] The following compounds were prepared using procedures similar to those described above: I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-15, I-16, I-17, I-18, I-19, I-20, I-21, I-22, I-23, I-24, I-25, I-26, I-27, I-28, I-29, I-30, I-31, I-32, I-33, I-34, I-35, I-36, I-37, I-38, I-39, I-40, I-41, I-42, I-43 and I-44.

[0896] Example 6 - Synthesis of N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[1-[[1-[4-[(9S)-9-[2-(ethylamino)-2-oxo-ethyl]-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]-4-piperidinyl]methyl]azetidin-3-yl]oxy-pyridazine-3-carboxamide (I-72)

[0897]

[0898]

[0899] Step 1: Preparation of tert-butyl 3-[6-[[4-(3-chloro-4-cyanophenoxy)cyclohexyl]carbamoyl]pyridazin-3-yl]oxyazetidine-1-carboxylate. At 0 °C, NaH (31 mg, 767 μmol, 60% purity, 1.5 equivalents) was added to a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (88 mg, 511 μmol, 1.0 equivalent, a known compound from WO2021 / 127443, 2021, A1) in THF (2 mL) for 0.5 h, and 6-chloro-N-[4-(3-chloro-4-cyanophenoxy)cyclohexyl]pyridazine-3-carboxamide (200 mg, 511 μmol, 1.0 equivalent) was added at 0 °C. The mixture was stirred at 20 °C for 12 h.

[0900] Step 2: Preparation of 6-(azetidin-3-yloxy)-N-[4-(3-chloro-4-cyanophenoxy)cyclohexyl]pyridazine-3-carboxamide. At 0 °C, 2,6-dimethylpyridine (313 mg, 2.9 mmol, 0.3 mL, 31 equivalents) and TMSOTf (315 mg, 1.42 mmol, 256 μL, 15.0 equivalents) were added to a solution of tert-butyl 3-[6-[[4-(3-chloro-4-cyanophenoxy)cyclohexyl]carbamoyl]pyridazin-3-yl]oxyazetidine-1-carboxylate (50 mg, 95 μmol, 1.0 equivalent) in DCM (2 mL), and then the solution was stirred at 0 °C for 0.5 h. The solution was quenched with 0.05 mL of H2O (25 equivalents) at 0 °C and the solution was used directly for the next step.

[0901] Step 3: Preparation of tert-butyl 2-[(9S)-7-[4-[4-(dimethoxymethyl)-1-piperidinyl]phenyl]-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetate. To 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2,6(tert-Butyl [[ID=13C-2(6),4,7,10,12-pentaen-9-yl]] acetate (500 mg, 1.09 mmol, 1.0 equiv)) and 4-(dimethoxymethyl)piperidine (261 mg, 1.64 mmol, 1.5 equiv) were added to a solution of Cs2CO3 (1.07 g, 3.28 mmol, 3.0 equiv) and SPhos Pd G3 (85 mg, 109 μmol, 0.1 equiv) in dioxane (10 mL). The mixture was stirred at 90 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (column: Waters Xbridge C18 150×50 mm×10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 48%-78%, 10 min) to afford [[ID=13C-2(6),4,7,10,12-pentaen-9-yl]] acetate (596 mg, 94% yield). 2,6 (tert-Butyl [[ID=13C-2(6),4,7,10,12-pentaen-9-yl]] acetate (596 mg, 94% yield).

[0902] Step 4: Preparation of 2-[(9S)-7-[4-(4-formyl-1-piperidinyl)phenyl]-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2,6 (tert-Butyl [[ID=13C-2(6),4,7,10,12-pentaen-9-yl]] acetate (60 mg, 103 μmol, 1.0 equiv)) in a solution of TFA (1 mL) and DCM (1 mL) was stirred for 1 h. The solution was concentrated under reduced pressure to give 2-[(9S)-7-[4-(4-formyl-1-piperidinyl)phenyl]-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2,6 ([[ID=13C-2(6),4,7,10,12-pentaen-9-yl]] acetate (61 mg, crude, TFA salt).

[0903] Step 5: Preparation of 2-[(9S)-7-[4-[4-[[3-[6-[[4-(3-chloro-4-cyanophenoxy)cyclohexyl]carbamoyl]pyridazin-3-yl]oxyazetidin-1-yl]methyl]-1-piperidinyl]phenyl]-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetic acid. To a solution of 2-[(9S)-7-[4-(4-formyl-1-piperidinyl)phenyl]-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2,6 trideca-2(6),4,7,10,12-pentaen-9-yl]acetic acid (61 mg, 103 μmol, 1.1 equiv., TFA salt) in DCM (4 mL) was added TEA (102 mg, 1.01 mmol, 10 equiv.) and 6-(azetidin-3-yloxy)-N-[4-(3-chloro-4-cyanophenoxy)cyclohexyl]pyridazine-3-carboxamide (53 mg, 98 μmol, 1.0 equiv., TFA salt) and NaBH(OAc)3 (145 mg, 685 μmol, 7.0 equiv.), and the solution was then stirred at 20 °C for 0.5 h. The solution was concentrated and purified by preparative HPLC (column: Waters Xbridge 150×25 mm×5 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 20%-50%, 8 min) to give 2-[(9S)-7-[4-[4-[[3-[6-[[4-(3-chloro-4-cyanophenoxy)cyclohexyl]carbamoyl]pyridazin-3-yl]oxyazetidin-1-yl]methyl]-1-piperidinyl]phenyl]-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2,6 trideca-2(6),4,7,10,12-pentaen-9-yl]acetic acid (26 mg, 30% yield) as a yellow solid.

[0904] Step 6: Preparation of N-[4-(3-chloro-4-cyanophenoxy)cyclohexyl]-6-[1-[[1-[4-[(9S)-9-[2-(ethylamino)-2-oxoethyl]-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]-4-piperidinyl]methyl]azetidin-3-yl]oxy]pyridazine-3-carboxamide. A solution of 2-[(9S)-7-[4-[4-[[3-[6-[[4-(3-chloro-4-cyanophenoxy)cyclohexyl]carbamoyl]pyridazin-3-yl]oxyazetidin-1-yl]methyl]-1-piperidinyl]phenyl]-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2,6 trideca-2(6),4,7,10,12-pentaen-9-yl]acetic acid (26 mg, 29 μmol, 1.0 equiv), ethylamine (4 mg, 88 μmol, 3.0 equiv), DIEA (15 mg, 115 μmol, 3.9 equiv), and HATU (17 mg, 44 μmol, 1.5 equiv) in DMF (0.5 mL) was stirred for 0.5 h. The solution was purified by preparative HPLC (column: Waters Xbridge C18 150×50 mm×10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 50%-80%, 10 min) to give N-[4-(3-chloro-4-cyanophenoxy)cyclohexyl]-6-[1-[[1-[4-[(9S)-9-[2-(ethylamino)-2-oxoethyl]-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2 ,6 trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]-4-piperidinyl]methyl]azetidin-3-yl]oxy]pyridazine-3-carboxamide (13 mg, 47% yield) as a white solid. 11H NMR (400 MHz, CDCl3): δ 8.24 (d, J = 8.8 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 8.8 Hz, 1H), 7.35 (d, J = 8.8 Hz, 2H), 7.16 (d, J = 8.8 Hz, 1H), 7.02 (d, J = 2.4 Hz, 1H), 6.91 - 6.78 (m, 3H), 6.50 (s, 1H), 5.55 - 5.45 (m, 1H), 4.60 - 4.50 (m, 1H), 4.43 - 4.27 (m, 1H), 4.19 - 4.03 (m, 1H), 3.95 - 3.90 (m, 2H), 3.84 - 3.73 (m, 2H), 3.59 - 3.51 (m, 1H), 3.44 - 3.22 (m, 5H), 2.87 - 2.62 (m, 5H), 2.54 - 2.36 (m, 5H), 2.29 - 2.14 (m, 4H), 1.85 - 1.80 (m, 2H), 1.77 - 1.69 (m, 5H), 1.56 - 1.44 (m, 3H), 1.38 - 1.25 (m, 2H), 1.19 (t, J = 7.2 Hz, 3H) LC-MS: MS (ES + ): RT = 1.473 min, m / z = 917.5 [M + H + ; LCMS method: 25

[0905] Example 7 - Synthesis of N-[4-(3-chloro-4-cyanophenoxy)cyclohexyl]-6-[4-[2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]ethyl]-1-piperidinyl]pyridazine-3-carboxamide (I-74)

[0906]

[0907]

[0908] Step 1: Preparation of 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2,6tert-Butyl [[(6E,10E,12E)-3,7,11-trimethyltrideca-2(6),4,7,10,12-pentaen-9-yl]acetate (1.0 g, 2.1 mmol, 1.0 equiv) was added to a solution of TFA (7.7 g, 67 mmol, 5.0 mL, 30 equiv) in DCM (10 mL). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was used directly in the next step to give compound 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2,6 trideca-2(6),4,7,10,12-pentaen-9-yl]acetic acid (877 mg, 99% yield).

[0909] Step 2: Preparation of 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamide. To a solution of 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2,6 trideca-2(6),4,7,10,12-pentaen-9-yl]acetic acid (877 mg, 2.19 mmol, 1.0 equiv) and NH4Cl (351 mg, 6.56 mmol, 3.0 equiv) in DMF (8 mL) was added HATU (915 mg, 2.41 mmol, 1.1 equiv) and DIEA (848 mg, 6.56 mmol, 3.0 equiv). The mixture was stirred at 25 °C for 1 h. The mixture was filtered and concentrated. The residue was purified by preparative HPLC (column: Waters XbridgeC18 150×50 mm×10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 24%-54%, 10 min) to give 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2,6 trideca-2(6),4,7,10,12-pentaen-9-yl]acetamide (740 mg, 84% yield).

[0910] Step 3: Preparation of 2-[[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole. A solution of 1,3-dioxol-2-one (103 mg, 1.20 mmol, 1.2 equiv) and 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2,6 trideca-2(6),4,7,10,12-pentaen-9-yl]acetamide (400 mg, 1.00 mmol, 1.0 equiv) in PPA (4 mL). The mixture was stirred at 160 °C for 3 h. The mixture was quenched by adding 50 mL of H2O at 0 °C and then diluted with 200 mL of EA. The mixture was extracted with H2O (15 mL × 2). The combined organic layers were washed with H2O (10 mL × 3), dried over [Na2SO4], filtered and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 2 / 1 to 0 / 1) to give the compound 2-[[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2,6 trideca-2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole (260 mg, 61% yield).

[0911] Step 4: Preparation of tert-butyl 4-[2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]ethynyl]piperidine-1-carboxylate. To a solution of 2-[[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole (400 mg, 943 μmol, 1.0 equiv), tert-butyl 4-ethynylpiperidine-1-carboxylate (237 mg, 1.13 mmol, 1.2 equiv), Cs2CO3 (614 mg, 1.89 mmol, 2.0 equiv) in DMF (4 mL), ACN (4 mL) was added [2-(2-aminophenyl)phenyl]palladium(1+); bis(1-adamantyl)-butyl-phosphane; methanesulfonate (69 mg, 94 μmol, 0.1 equiv). The mixture was stirred at 90 °C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. By flash silica gel chromatography ( 5G The residue was purified by silica gel flash column with an eluent of 100% ethyl acetate / petroleum ether gradient at 18 mL / min to obtain tert-butyl 4-[2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]ethynyl]piperidine-1-carboxylate as a yellow solid (460 mg, 770 μmol, 81% yield).

[0912] Step 5: Preparation of tert-butyl 4-[2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]ethyl]piperidine-1-carboxylate. A mixture of tert-butyl 4-[2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]ethynyl]piperidine-1-carboxylate (410 mg, 687 μmol, 1.0 equiv), Pd / C (200 mg, 687 μmol, 10% purity, 1.0 equiv) in MeOH (5 mL) was degassed and purged with H2 three times, then the mixture was stirred under H2 atmosphere at 25 °C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue which was used directly in the next step. tert-Butyl 4-[2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]ethyl]piperidine-1-carboxylate was obtained as a yellow solid (305 mg, 507 μmol, 73% yield).

[0913] Step 6: Preparation of 2-[[(9S)-4,5,13-trimethyl-7-[4-[2-(4-piperidinyl)ethyl]phenyl]-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole. A mixture of tert-butyl 4-[2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]ethyl]piperidine-1-carboxylate (280 mg, 466 μmol, 1.0 equiv) in DCM (3 mL) and TFA (1 mL) was degassed and purged with N2 three times, and then the mixture was stirred under a N2 atmosphere at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue which was used directly in the next step. The compound 2-[[(9S)-4,5,13-trimethyl-7-[4-[2-(4-piperidinyl)ethyl]phenyl]-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole was obtained as a yellow oil (286 mg, 465 μmol, 99% yield, TFA).

[0914] Step 7: Preparation of N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[4-[2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]ethyl]-1-piperidinyl]pyridazine-3-carboxamide. A mixture of 2-[[(9S)-4,5,13-trimethyl-7-[4-[2-(4-piperidinyl)ethyl]phenyl]-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole (143 mg, 285 μmol, 1.0 equiv), 6-chloro-N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]pyridazine-3-carboxamide (89 mg, 228 μmol, 0.8 equiv), and K2CO3 (118 mg, 856 μmol, 3.0 equiv) in DMF (1.5 mL) was degassed and purged with N2 three times, and then the mixture was stirred under a N2 atmosphere at 60 °C for 2 h. The reaction mixture was filtered. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150×25 mm×10 μm; mobile phase: [water (FA)-ACN]; B%: 63%-93%, 8 min) to give N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[4-[2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]ethyl]-1-piperidinyl]pyridazine-3-carboxamide as a yellow solid (86 mg, 87 μmol, 30% yield, 98% purity, TFA). 11H NMR: (400 MHz, MeOD) δ = 8.44 (s, 1H), 7.92 - 7.84 (m, 2H), 7.69 (d, J = 8.8 Hz, 1H), 7.32 - 7.22 (m, 5H), 7.20 (d, J = 2.4 Hz, 1H), 7.13 (s, 1H), 7.08 - 7.01 (m, 1H), 4.79 - 4.74 (m, 3H), 4.59 (s, 2H), 4.49 (d, J = 12.8 Hz, 3H), 4.00 - 3.95 (m, 2H), 3.05 - 2.94 (m, 2H), 2.75 - 2.72 (m, 1H), 2.71 (s, 3H), 2.45 (s, 3H), 2.25 - 2.16 (m, 2H), 2.13 - 2.05 (m, 2H), 1.93 - 1.84 (m, 2H), 1.67 (s, 3H), 1.64 (s, 2H), 1.61 (s, 2H), 1.34 - 1.19 (m, 3H). LC-MS: MS(ES+): RT = 2.850 min, m / z = 855.6 [M+H + ; LCMS method: 25.

[0915] Example 8 - Synthesis of N-[4-(3-chloro-4-cyanophenoxy)cyclohexyl]-6-[2-[[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]methyl]-2,7-diazaspiro[3.5]nonan-7-yl]pyridazine-3-carboxamide (I-109)

[0916]

[0917] Step 1: Preparation of (7-tert-butoxycarbonyl-2,7-diazaspiro[3.5]nonan-2-yl)methyl-trifluoro-borate; potassium hydride. Potassium bromomethyl(trifluoro)borate (728 mg, 3.6 mmol, 1.0 equivalent) was added to a solution of tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate; hydrochloride (1.0 g, 3.8 mmol, 1.1 equivalents) in THF (6 mL). The mixture was stirred at 80 °C for 3 hours. After concentration, the residue was suspended in ACN (21 mL) and combined with K2CO3 (501 mg, 3.6 mmol, 1.0 equivalent). The mixture was stirred at 25 °C for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was used in the next step without further purification. (7-tert-butoxycarbonyl-2,7-diazaspiro[3.5]nonan-2-yl)methyl-trifluoro-borate; potassium hydride was obtained as a white foam (1 g, 3.2 mmol, 88% yield).

[0918] Step 2: Preparation of tert-butyl 2-[[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]methyl]-2,7-diazaspiro[3.5]nonane-7-carboxylate. To a solution of 2-[[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole (400 mg, 943.6 μmol, 1.0 equiv), (7-tert-butoxycarbonyl-2,7-diazaspiro[3.5]non-2-yl)methyl-trifluoro-bor; potassium hydride (490 mg, 1.4 mmol, 1.5 equiv) in THF (6 mL) and H2O (3 mL) was added Pd(OAc)2 (11 mg, 47.2 μmol, 0.05 equiv) and XPhos (45 mg, 94.4 μmol, 0.1 equiv), Cs2CO3 (922 mg, 2.8 mmol, 3.0 equiv). The mixture was stirred at 90 °C for 12 h. The residue was diluted with 30 mL of water and extracted with EA (20 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge C18 150×50 mm×10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 39%-69%, 10 min). The compound tert-butyl 2-[[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]methyl]-2,7-diazaspiro[3.5]nonane-7-carboxylate was obtained as a white solid (225 mg, 358.4 μmol, 38% yield).

[0919] Step 3: Preparation of 2-[[(9S)-7-[4-(2,7-diazaspiro[3.5]nonan-2-ylmethyl)phenyl]-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole. To a solution of tert-butyl 2-[[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]methyl]-2,7-diazaspiro[3.5]nonane-7-carboxylate (225 mg, 358 μmol, 1.0 equiv) in DCM (1 mL) was added TFA (0.5 mL). The reaction mixture was concentrated under reduced pressure to afford 2-[[(9S)-7-[4-(2,7-diazaspiro[3.5]nonan-2-ylmethyl)phenyl]-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole as a colorless oil (225 mg, 358 μmol, 99% yield, TFA salt).

[0920] Step 4: Preparation of N-[4-(3-chloro-4-cyanophenoxy)cyclohexyl]-6-[2-[[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]methyl]-2,7-diazaspiro[3.5]non-7-yl]pyridazine-3-carboxamide. A solution of tert-butyl 2-[(9S)-7-[4-[4-(dimethoxymethyl)-1-piperidinyl]phenyl]-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2,6 trideca-2(6),4,7,10,12-pentaen-9-yl]acetate (60 mg, 103 μmol, 1.0 equiv) in TFA (1 mL) and DCM (1 mL) was stirred for 1 h. The solution was concentrated under reduced pressure to afford 2-[(9S)-7-[4-(4-formyl-1-piperidinyl)phenyl]-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2,6(61 mg, crude, TFA salt) of [(6E,10E)-3,7,11-trimethyl-15-oxo-13-oxa-2,6,10,14-tetraazapentadeca-1,6,10-triene-4-yl] acetate. To a solution of 2-[[(9S)-7-[4-(2,7-diazaspiro[3.5]nonan-2-ylmethyl)phenyl]-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole (140 mg, 265 μmol, 1.0 equiv), 6-chloro-N-[4-(3-chloro-4-cyanophenoxy)cyclohexyl]pyridazine-3-carboxamide (104 mg, 265 μmol, 1.0 equiv) in NMP (1.5 mL) was added K2CO3 (110 mg, 796 μmol, 3.0 equiv). The mixture was stirred at 50 °C for 12 h. After filtration, the filtrate was purified by preparative HPLC (column: Phenomenex luna C18 150×25 mm×10 μm; mobile phase: [water (FA)-ACN]; B%: 24%-54%, 10 min) to give N-[4-(3-chloro-4-cyanophenoxy)cyclohexyl]-6-[2-[[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]methyl]-2,7-diazaspiro[3.5]non-7-yl]pyridazine-3-carboxamide (129 mg, 143 μmol, 54% yield, 98% purity) as a yellow solid. 1 H NMR (400 MHz, CD3OD) 7.86 - 7.92 (m, 2H) 7.65 - 7.71 (m, 1H) 7.42 - 7.48 (m, 4H) 7.26 - 7.33 (m, 1H) 7.17 - 7.22 (m, 1H) 7.10 - 7.15 (m, 1H) 7.01 - 7.07 (m, 1H) 4.75 - 4.81 (m, 1H) 4.45 - 4.56 (m, 1H) 4.10 - 4.18 (m, 2H) 3.90 - 4.06 (m, 3H) 3.57 - 3.79 (m, 8H) 2.66 - 2.75 (m, 3H) 2.43 - 2.47 (m, 3H) 2.15 - 2.24 (m, 2H) 2.04 - 2.14 (m, 2H) 1.88 - 1.95 (m, 4H) 1.57 - 1.70 (m, 7H). LC-MS: MS (ES + ): RT = 2.070 min, m / z = 882.4 [M+H + ; LCMS method: 10.

[0921] Example 9- Synthesis of N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]-2,7-diazaspiro[3.5]non-7-yl]pyridazine-3-carboxamide (I-132)

[0922]

[0923] Step 1: Preparation of tert-butyl 2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]-2,7-diazaspiro[3.5]nonane-7-carboxylate. To a solution of 2-[[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole (210 mg, 495 μmol, 1.0 equiv) and tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate; hydrochloride (195 mg, 743 μmol, 1.5 equiv) in dioxane (5 mL) was added SPhos Pd G3 (77.3 mg, 99.1 μmol, 0.2 equiv) and Cs2CO3 (484 mg, 1.49 mmol, 3.0 equiv). The mixture was stirred at 90 °C for 12 h. The residue was diluted with H2O (50 mL) and extracted with EA (20 mL × 3). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150×25 mm×10 μm; mobile phase: [water (FA)-ACN]; B%: 42%-72%, 10 min) to give tert-butyl 2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]-2,7-diazaspiro[3.5]nonane-7-carboxylate as a yellow oil (270 mg, 440 μmol, 89% yield).

[0924] Step 2: Preparation of 2-[[(9S)-7-[4-(2,7-diazaspiro[3.5]nonan-2-yl)phenyl]-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole. To a solution of tert-butyl 2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]-2,7-diazaspiro[3.5]nonane-7-carboxylate (110 mg, 179 μmol, 1.0 equiv) in DCM (2 mL) was added TFA (1 mL). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated to give 2-[[(9S)-7-[4-(2,7-diazaspiro[3.5]nonan-2-yl)phenyl]-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole (113 mg, crude, TFA salt) as a yellow oil and was used in the next step without further purification.

[0925] Step 3: Preparation of N-[4-(3-chloro-4-cyanophenoxy)cyclohexyl]-6-[2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]-2,7-diazaspiro[3.5]non-7-yl]pyridazine-3-carboxamide. To a solution of 2-[[(9S)-7-[4-(2,7-diazaspiro[3.5]non-2-yl)phenyl]-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole (164 mg, 261 μmol, 1.0 equiv., TFA salt) and 6-chloro-N-[4-(3-chloro-4-cyanophenoxy)cyclohexyl]pyridazine-3-carboxamide (112 mg, 287 μmol, 1.1 equiv.) in NMP (2 mL) was added K2CO3 (108 mg, 784 μmol, 3.0 equiv.). The mixture was stirred at 50 °C for 12 h. After filtration, the filtrate was purified by preparative HPLC (column: Phenomenex luna C18 150×25 mm×10 μm; mobile phase: [water (FA)-ACN]; B%: 54%-74%, 10 min) to give N-[4-(3-chloro-4-cyanophenoxy)cyclohexyl]-6-[2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]-2,7-diazaspiro[3.5]non-7-yl]pyridazine-3-carboxamide as a yellow solid (70 mg, 77 μmol, 30% yield, 96% purity). 11H NMR (400 MHz, CD3OD) δ 7.94 - 7.89 (m, 2H), 7.69 (d, J = 8.8 Hz, 1H), 7.34 (br t, J = 9.2 Hz, 3H), 7.20 (d, J = 2.3 Hz, 1H), 7.15 (s, 1H), 7.07 - 7.02 (m, 1H), 6.52 - 6.46 (m, 2H), 4.95 - 4.88 (m, 2H), 4.05 - 3.95 (m, 3H), 3.88 - 3.77 (m, 8H), 2.73 (s, 3H), 2.49 (s, 3H), 2.25 - 2.17 (m, 2H), 2.11 (br d, J = 3.8 Hz, 2H), 1.96 (br d, J = 4.0 Hz, 4H), 1.82 - 1.76 (m, 3H), 1.69 - 1.59 (m, 4H). LC-MS: MS (ES + ): RT = 2.243 min, m / z = 868.4 [M+H + ; LCMS method: 10.

[0926] Example 10 - Synthesis of N-[4-(3-chloro-4-cyanophenoxy)cyclohexyl]-6-[2-[4-[(9E)-4,5,13-trimethyl-9-(oxazol-2-ylmethylene)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro[3.5]nonan-7-yl]pyridazine-3-carboxamide (I-135)

[0927]

[0928] Step 1: Preparation of tert-butyl 2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro[3.5]nonane-7-carboxylate. To a solution of 2-[[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole (300 mg, 707 μmol, 1.0 equiv), tert-butyl 2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate (853 mg, 3.54 mmol, 5.0 equiv) in dioxane (5 mL) was added tBuXPhos Pd G3 (112 mg, 141 μmol, 0.2 equiv) and Cs2CO3 (1.1 g, 3.5 mmol, 5.0 equiv). The mixture was degassed and purged with N2 three times, then the mixture was stirred under a N2 atmosphere at 90 °C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica chromatography ( 2 g silica flash column, eluent 0 - 3% methanol / dichloromethane gradient, 18 mL / min) to afford tert-butyl 2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro[3.5]nonane-7-carboxylate as a yellow solid (210 mg, 333 μmol, 47% yield).

[0929] Step 2: Preparation of tert-butyl 2-[4-[(9Z)-4,5,13-trimethyl-9-(oxazol-2-ylmethylene)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro[3.5]nonane-7-carboxylate. A mixture of tert-butyl 2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro[3.5]nonane-7-carboxylate (200 mg, 318 μmol, 1.0 equiv), Pd(OAc)2 (22 mg, 96 μmol, 0.3 equiv), K2CO3 (66 mg, 477 μmol, 1.5 equiv) and dcpp (83 mg, 191 μmol, 0.6 equiv) in DMSO (2 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 120 °C under a N2 atmosphere for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150×25 mm×10 μm; mobile phase: [water (FA)-ACN]; gradient: 69%-99% B over 10 min) to give tert-butyl 2-[4-[(9Z)-4,5,13-trimethyl-9-(oxazol-2-ylmethylene)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro[3.5]nonane-7-carboxylate as a yellow solid (60 mg, 96 μmol, 30% yield).

[0930] Step 3: Preparation of 2-[(E)-[7-[4-(7-azaspiro[3.5]nonan-2-yloxy)phenyl]-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-ylidene]methyl]oxazole. A mixture of tert-butyl 2-[4-[(9E)-4,5,13-trimethyl-9-(oxazol-2-ylmethylene)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro[3.5]nonane-7-carboxylate (50 mg, 80 μmol, 1.0 eq) in DCM (3 mL) and TFA (1 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 25 °C under a N2 atmosphere for 2 h. The reaction mixture was concentrated under reduced pressure to give 2-[(E)-[7-[4-(7-azaspiro[3.5]nonan-2-yloxy)phenyl]-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-ylidene]methyl]oxazole as a colorless oil (51 mg, 80 μmol, 100% yield, TFA).

[0931] Step 4: Preparation of N-[4-(3-chloro-4-cyanophenoxy)cyclohexyl]-6-[2-[4-[(9E)-4,5,13-trimethyl-9-(oxazol-2-ylmethylene)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro[3.5]non-7-yl]pyridazine-3-carboxamide. A mixture of 2-[(E)-[7-[4-(7-azaspiro[3.5]non-2-yloxy)phenyl]-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-ylidene]methyl]oxazole (70 mg, 110 μmol, 1.0 equivalent, TFA), 6-chloro-N-[4-(3-chloro-4-cyanophenoxy)cyclohexyl]pyridazine-3-carboxamide (47 mg, 120 μmol, 1.1 equivalents), and K2CO3 (151 mg, 1 mmol, 10.0 equivalents) in NMP (2 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 25 °C under a N2 atmosphere for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge 150×25 mm×5 μm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 54%-84% B over 10 min) to give N-[4-(3-chloro-4-cyanophenoxy)cyclohexyl]-6-[2-[4-[(9E)-4,5,13-trimethyl-9-(oxazol-2-ylmethylene)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro[3.5]non-7-yl]pyridazine-3-carboxamide as a yellow solid (37 mg, 39 μmol, 36% yield). 11H NMR: (400 MHz, MeOD) δ = 8.07 (s, 1H), 7.89 (d, J = 9.6 Hz, 1H), 7.79 - 7.71 (m, 2H), 7.69 (d, J = 8.8 Hz, 1H), 7.39 - 7.33 (m, 1H), 7.30 (d, J = 9.6 Hz, 1H), 7.22 - 7.17 (m, 1H), 7.08 - 7.02 (m, 1H), 6.99 - 6.93 (m, 2H), 6.44 (s, 1H), 4.58 (s, 1H), 4.55 - 4.46 (m, 1H), 4.02 - 3.91 (m, 1H), 3.82 - 3.77 (m, 2H), 3.75 - 3.69 (m, 2H), 2.77 (s, 3H), 2.63 - 2.54 (m, 2H), 2.41 (s, 3H), 2.25 - 2.16 (m, 2H), 2.15 - 2.07 (m, 2H), 2.07 - 1.98 (m, 3H), 1.83 - 1.74 (m, 4H), 1.72 (s, 3H), 1.68 - 1.61 (m, 4H). LC-MS: MS(ES + ): RT = 2.689 min, m / z = 881.4 [M + H + ; LCMS method: 25

[0932] Example 11 - Synthesis of N-[4-(3-chloro-4-cyanophenoxy)cyclohexyl]-6-[4-[3-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]prop-2-ynyl]-1-piperidinyl]pyridazine-3-carboxamide (I-136)

[0933]

[0934] Step 1: Preparation of tert-butyl 4-prop-2-ynylpiperidine-1-carboxylate. A mixture of tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (5 g, 22.0 mmol, 1.0 equiv), 1-diazo-1-dimethoxyphosphoryl-propan-2-one (5.5 g, 28.6 mmol, 1.3 equiv), and K2CO3 (6.1 g, 43.9 mmol, 2.0 equiv) in MeOH (50 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 20 °C under a N2 atmosphere for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1) to give tert-butyl 4-prop-2-ynylpiperidine-1-carboxylate (4.4 g, 90% yield).

[0935] Step 2: Preparation of the crude substance tert-butyl 4-[3-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]prop-2-ynyl]piperidine-1-carboxylate. A mixture of tert-butyl 4-prop-2-ynylpiperidine-1-carboxylate (869 mg, 3.9 mmol, 3.0 equiv), 2-[[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole (550 mg, 1.3 mmol, 1.0 equiv), Cs2CO3 (845.5 mg, 2.6 mmol, 2.0 equiv), [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium; 2-(2-dicyclohexylphosphanyl)phenyl)-N,N-dimethyl-aniline (99 mg, 129 μmol, 0.1 equiv) in ACN (15 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 90 °C under a N2 atmosphere for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, DCM:MEOD to 10 / 1) to give tert-butyl 4-[3-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]prop-2-ynyl]piperidine-1-carboxylate (460 mg, 58% yield).

[0936] Step 3: Preparation of crude 2-[[(9S)-4,5,13-trimethyl-7-[4-[3-(4-piperidinyl)prop-1-ynyl]phenyl]-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole. To a solution of tert-butyl 4-[3-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]prop-2-ynyl]piperidine-1-carboxylate (460 mg, 753 μmol, 1.0 equiv) in DCM (5 mL) was added TFA (85 mg, 753 μmol, 55 μL, 1.0 equiv). The mixture was stirred at 25 °C for 1 h. The reaction mixture was filtered and the filtrate was concentrated. The product was used directly in the next step.

[0937] Step 4: Preparation of crude N-[4-(3-chloro-4-cyanophenoxy)cyclohexyl]-6-[4-[3-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]prop-2-ynyl]-1-piperidinyl]pyridazine-3-carboxamide. To a solution of 2-[[(9S)-4,5,13-trimethyl-7-[4-[3-(4-piperidinyl)prop-1-ynyl]phenyl]-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole (200 mg, 390 μmol, 1.0 equiv), 6-chloro-N-[4-(3-chloro-4-cyanophenoxy)cyclohexyl]pyridazine-3-carboxamide (153 mg, 391 μmol, 1.0 equiv) in NMP (3 mL) was slowly added DIEA (101 mg, 783 μmol, 136 μL, 2.0 equiv). The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by preparative TLC (SiO2, DCM:MeOH = 10:1). The product was used directly in the next step.

[0938] Step 5: Preparation of N-[4-(3-chloro-4-cyanophenoxy)cyclohexyl]-6-[4-[3-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]prop-2-ynyl]-1-piperidinyl]pyridazine-3-carboxamide. The residue was purified by preparative SFC (EW30421-752-P1A1) (column: DAICEL CHIRALPAK AS (250 mm × 30 mm, 10 um); mobile phase: [CO2-ACN / MeOH (0.1% NH3H2O)]; B%: 65%, isocratic elution mode) to obtain N-[4-(3-chloro-4-cyanophenoxy)cyclohexyl]-6-[4-[3-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2,6 trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]prop-2-ynyl]-1-piperidinyl]pyridazine-3-carboxamide (83 mg, 23% yield) (Rt = 2.538 min). 1 H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 9.2 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.64 (s, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.38 - 7.31 (m, 4H), 7.05 (s, 1H), 7.03 - 6.96 (m, 2H), 6.86 (s, 1H), 4.74 (t, J = 7.2 Hz, 1H), 4.56 (s, 2H), 4.38 - 4.28 (m, 1H), 4.18 - 4.07 (m, 2H), 4.07 - 4.02 (m, 1H), 3.07 (s, 2H), 2.69 (s, 3H), 2.47 - 2.43 (m, 2H), 2.41 (s, 3H), 2.19 (s, 4H), 2.02 (s, 2H), 1.99 - 1.90 (m, 1H), 1.71 (s, 2H), 1.65 - 1.63 (m, 2H), 1.54 - 1.38 (m, 5H). LC-MS: MS (ES + ): RT = 2.472 min, m / z = 865.4 [M+H + ; LCMS method: 25

[0939] Example 12- Synthesis of N-[4-(3-chloro-4-cyanophenoxy)cyclohexyl]-6-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]pyridazine-3-carboxamide (I-141)

[0940]

[0941] Step 1: Preparation of 4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenol. A mixture of 2-[[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole (5.8 g, 13.7 mmol, 1.0 equiv), BrettPhos Pd G3 (1.2 g, 1.4 mmol, 0.1 equiv), and KOH (3.8 g, 68.4 mmol, 5.0 equiv) in dioxane (58 mL) and H2O (11.6 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 90 °C under a N2 atmosphere for 3 h. The reaction mixture was partitioned between ethyl acetate (2000 mL) and water (500 mL). The organic phase was separated, washed with brine (500 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, dichloromethane:methanol = 40 / 1) to give 4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenol as a yellow solid (3.5 g, 8.6 mmol, 63% yield).

[0942] Step 2: Preparation of N-[4-(3-chloro-4-cyanophenoxy)cyclohexyl]-6-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]pyridazine-3-carboxamide. To a solution of 6-chloro-N-[4-(3-chloro-4-cyanophenoxy)cyclohexyl]pyridazine-3-carboxamide (96 mg, 247 μmol, 1.0 equiv) in NMP (2 mL) was added K2CO3 (102 mg, 740 μmol, 3.0 equiv) and 4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenol (100 mg, 247 μmol, 1.0 equiv). The mixture was stirred at 50 °C for 12 h. The mixture was concentrated to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge 150×25 mm×5um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 46%-76% B over 10 min) to give N-[4-(3-chloro-4-cyanophenoxy)cyclohexyl]-6-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]pyridazine-3-carboxamide as a white solid (95 mg, 51% yield, 99% purity). 1 1H NMR (400 MHz, CDCl3): δ 8.33 (d, J = 9.2 Hz, 1H), 7.92 - 7.83 (m, 1H), 7.65 (s, 1H), 7.55 (m, J = 8.8, 13.6 Hz, 3H), 7.33 (d, J = 9.2 Hz, 1H), 7.22 (d, J = 8.8 Hz, 2H), 7.06 (s, 1H), 7.00 (d, J = 2.4 Hz, 1H), 6.86 (m, J = 2.4, 8.8 Hz, 1H), 4.78 (t, J = 7.2 Hz, 1H), 4.37 - 4.27 (m, 1H), 4.17 - 4.03 (m, 3H), 2.70 (s, 3H), 2.43 (s, 3H), 2.24 - 2.14 (m, 4H), 1.78 (s, 3H), 1.73 - 1.66 (m, 2H), 1.52 - 1.43 (m, 2H). LC-MS: MS (ES + ): RT = 2.592 min, m / z = 760.2 [M+H+ ; LCMS method: 10.

[0943] Example 13 - Synthesis of N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[2-[[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]methylene]-6-azaspiro[3.5]non-6-yl]pyridazine-3-carboxamide (I-142)

[0944]

[0945]

[0946] Step 1: Preparation of tert-butyl 2-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene]-6-azaspiro[3.5]nonane-6-carboxylate. To a solution of TMP (2.2 g, 16 mmol, 2.7 mL, 2.0 equiv) in THF (12 mL) at -30 °C was added n-BuLi (2.5 M, 6.4 mL, 2.0 equiv), and the solution was then stirred at -30 °C for 0.5 h. A solution of 4,4,5,5-tetramethyl-2-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl]-1,3,2-dioxaborolane (3.2 g, 12 mmol, 1.5 equiv) in THF (4 mL) was added to the solution at -70 °C. The mixture was stirred at -70 °C for 0.5 h. A solution of tert-butyl 2-oxo-6-azaspiro[3.5]nonane-6-carboxylate (1.9 g, 8.0 mmol, 1.0 equiv) in THF (4 mL) was added to the mixture at -70 °C, and the mixture was stirred at -70 °C for 2 h. Then it was stirred at 25 °C for 12 h and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 10 / 1) to give tert-butyl 2-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene]-6-azaspiro[3.5]nonane-6-carboxylate as a colorless oil (1.7 g, 59% yield).

[0947] Step 2: Preparation of crude 2-[[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]methylene]-6-azaspiro[3.5]nonane-6-carboxylic acid tert-butyl ester. A mixture of 2-[[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole (600 mg, 1.4 mmol, 1.0 equiv), 2-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene]-6-azaspiro[3.5]nonane-6-carboxylic acid tert-butyl ester (1 g, 2.8 mmol, 2.0 equiv), SPhos Pd G3 (110 mg, 142 μmol, 0.1 equiv) and Cs2CO3 (461 mg, 1.4 mmol, 1.0 equiv) in DMF (10 mL) was degassed and purged with N2 three times. The mixture was stirred at 90 °C under N2 atmosphere for 12 h and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 0 / 1) to give 2-[[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]methylene]-6-azaspiro[3.5]nonane-6-carboxylic acid tert-butyl ester as a yellow oil (700 mg, 79% yield).

[0948] Step 3: Preparation of crude substance 2-[[(9S)-7-[4-(6-azaspiro[3.5]non-2-ylidene-methyl)phenyl]-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole. To a solution of tert-butyl 2-[[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]methylene]-6-azaspiro[3.5]nonane-6-carboxylate (700 mg, 1 mmol, 1.0 equiv) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure to give a residue. The residue was diluted with 10 mL of DCM and the pH was adjusted to 7 - 8 with saturated aqueous NaHCO3, then extracted with DCM (20 mL × 3), and the combined organic layers were concentrated under reduced pressure to give the crude product.

[0949] Step 4: Preparation of crude N-[4-(3-chloro-4-cyanophenoxy)cyclohexyl]-6-[2-[[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]methylene]-6-azaspiro[3.5]non-6-yl]pyridazine-3-carboxamide. To a solution of 2-[[(9S)-7-[4-(6-azaspiro[3.5]non-2-ylmethyl)phenyl]-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole (330 mg, 629 μmol, 1.0 equiv) in NMP (4.5 mL) was added DIEA (162 mg, 1.26 mmol, 219 μL, 2.0 equiv) and 6-chloro-N-[4-(3-chloro-4-cyanophenoxy)cyclohexyl]pyridazine-3-carboxamide (246 mg, 629 μmol, 1.0 equiv). The mixture was stirred at 50 °C for 12 h. The solution was diluted with water (5 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, ethyl acetate:MeOH = 10:1) to give the crude N-[4-(3-chloro-4-cyanophenoxy)cyclohexyl]-6-[2-[[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]methylene]-6-azaspiro[3.5]non-6-yl]pyridazine-3-carboxamide as a yellow solid (190 mg, 34% yield).

[0950] Step 5: Preparation of N-[4-(3-chloro-4-cyanophenoxy)cyclohexyl]-6-[2-[[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]methylene]-6-azaspiro[3.5]non-6-yl]pyridazine-3-carboxamide. Purify N-[4-(3-chloro-4-cyanophenoxy)cyclohexyl]-6-[2-[[4-[4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]methylene]-6-azaspiro[3.5]non-6-yl]pyridazine-3-carboxamide (190 mg, 216 μmol, 1.0 eq) by SFC (column: DAICEL CHIRALPAK AS (250 mm × 30 mm, 10 μm); mobile phase: [CO2 - ACN / MeOH (0.1% NH3H2O)]; B%: 50%, isocratic elution mode) to obtain N-[4-(3-chloro-4-cyanophenoxy)cyclohexyl]-6-[2-[[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]methylene]-6-azaspiro[3.5]non-6-yl]pyridazine-3-carboxamide as a yellow solid (81 mg, 42% yield). 1 H NMR (400 MHz, CDCl3) δ 7.99 - 7.91 (m, 1H), 7.89 - 7.80 (m, 1H), 7.63 (s, 1H), 7.60 - 7.51 (m, 1H), 7.37 - 7.29 (m, 2H), 7.19 - 7.10 (m, 2H), 7.08 - 6.94 (m, 3H), 6.90 - 6.82 (m, 1H), 6.26 - 6.18 (m, 1H), 4.80 - 4.65 (m, 1H), 4.40 - 4.26 (m, 1H), 4.17 - 3.98 (m, 3H), 3.86 - 3.73 (m, 2H), 3.71 - 3.59 (m, 2H), 2.88 - 2.54 (m, 7H), 2.46 - 2.33 (m, 3H), 2.26 - 2.09 (m, 4H), 1.86 - 1.78 (m, 2H), 1.71 - 1.62 (m, 6H), 1.53 - 1.37 (m, 2H). LC-MS: MS(ES + ): RT = 2.566 min, m / z = 879.4 [M + H+ ; LCMS method: 25.

[0951] Example 14 - Synthesis of additional compounds

[0952] The following compounds were synthesized using procedures similar to those described above: I-45, I-46, I-47, I-48, I-49, I-50, I-51, I-52, I-53, I-54, I-55, I-56, I-57, I-58, I-59, I-60, I-61, I-62, I-63, I-64, I-65, I-66, I-67, I-68, I-69, I-70, I-71, I-73, I-75, I-76, I-77, I-78, I-79, I-80, I-81, I-82, I-83, I-84, I-85, I-86, I-87, I-88, I-89, I-90, I-91, I-92, I-93, I-94, I-95, I-96, I-97, I-98, I-101, I-102, I-103, I-104, I-105, I-106, I-107, I-108, I-110, I-111, I-112, I-113, I-114, I-115, I-116, I-117, I-118, I-119, I-120, I-121, I-122, I-123, I-124, I-125, I-126, I-127, I-128, I-129, I-130, I-131, I-133, I-134, I-137, I-138, I-139, I-140 and I-143.

[0953] Example 15 - Compound characterization

[0954] Exemplary compounds were characterized by LCMS. The characterization data are summarized in Table 2 below.

[0955] Table 2.

[0956]

[0957]

[0958]

[0959]

[0960] Example 16- Synthesis of N-[4-(3-chloro-4-cyanophenoxy)cyclohexyl]-6-[8-[4-[(9S)-4,5,9,13-tetramethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]-2-azaspiro[4.4]non-2-yl]pyridazine-3-carboxamide (I-821)

[0961]

[0962] Step 1: Preparation of tert-butyl 8-(4-chlorophenyl)-2-azaspiro[4.4]non-7-ene-2-carboxylate. A mixture of tert-butyl 8-(trifluoromethylsulfonyloxy)-2-azaspiro[4.4]non-7-ene-2-carboxylate (2.0 g, 5.4 mmol, 1.0 equiv), (4-chlorophenyl)boronic acid (1.1 g, 7.0 mmol, 1.3 equiv), Pd(PPh3)2Cl2 (378 mg, 539 μmol, 0.1 equiv), and NaHCO3 (905 mg, 10.8 mmol, 419 μL, 2.0 equiv) in THF (20 mL) and H2O (6 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 65 °C under a N2 atmosphere for 12 h. The reaction mixture was partitioned between 100 mL of ethyl acetate and 200 mL of H2O (100 mL × 2). The organic phase was separated, washed with 100 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to give tert-butyl 8-(4-chlorophenyl)-2-azaspiro[4.4]non-7-ene-2-carboxylate as a yellow solid (2.5 g, 5.2 mmol, 96% yield).

[0963] Step 2: Preparation of tert-butyl 8-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-azaspiro[4.4]non-7-ene-2-carboxylate. A mixture of tert-butyl 8-(4-chlorophenyl)-2-azaspiro[4.4]non-7-ene-2-carboxylate (2.5 g, 7.4 mmol, 1.0 equiv), BPD (2.8 g, 11.1 mmol, 1.5 equiv), KOAc (2.2 g, 22.1 mmol, 3.0 equiv), XPhos (527 mg, 1.1 mmol, 0.15 equiv) and Pd2(dba)3 (337 mg, 368 μmol, 0.05 equiv) in dioxane (25 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 70 °C under a N2 atmosphere for 12 h. The reaction mixture was partitioned between 100 mL of ethyl acetate and 200 mL of H2O (100 mL × 2). The resulting organic phase was separated, washed with 100 mL of brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge C18 150 × 50 mm × 10 um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 70%-100% B over 10 min) to give tert-butyl 8-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-azaspiro[4.4]non-7-ene-2-carboxylate as a yellow solid (2.0 g, 4.7 mmol, 64% yield).

[0964] Step 3: Preparation of tert-butyl 8-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-azaspiro[4.4]nonane-2-carboxylate. Pd / C (1.5 g, 14.1 mmol, 10% purity, 4.0 equiv) was added to a solution of tert-butyl 8-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-azaspiro[4.4]non-7-ene-2-carboxylate (1.5 g, 3.5 mmol, 1.0 equiv) in MeOH (15 mL). The mixture was stirred at 50 °C under H2 (50 psi) for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give tert-butyl 8-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-azaspiro[4.4]nonane-2-carboxylate as a white oil (1.4 g, 3.4 mmol, 96% yield).

[0965] Step 4: Preparation of tert-butyl 8-[4-[(9S)-4,5,9,13-tetramethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]-2-azaspiro[4.4]nonane-2-carboxylate. tert-Butyl 8-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-azaspiro[4.4]nonane-2-carboxylate (1.0 g, 2.3 mmol, 1.0 equiv), (9S)-7-chloro-4,5,9,13-tetramethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaene (985 mg, 3.5 mmol, 1.5 equiv), Pd(dppf)Cl2 (171 mg, 234 μmol, 0.1 equiv), and Cs2CO3 (2.3 g, 7.0 mmol, 3.0 equiv) in a mixture of THF (10 mL) and H2O (4 mL) were degassed and purged with N2 three times, and then the mixture was stirred at 50 °C under a N2 atmosphere for 3 h. The reaction mixture was partitioned between 100 mL of ethyl acetate and 200 mL of H2O (100 mL × 2). The organic phase was separated, washed with 100 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (S...

Claims

1. A compound represented by formula I: or a pharmaceutically acceptable salt thereof; wherein: R 1 is a phenyl group substituted by a cyano group, a halogen, and R occurring m times 4 substituted phenyl; R 2 and R 3 are independently hydrogen or C 1-4 alkyl; R 4 is C 1-4 alkyl; R 5 independently represents C at each occurrence 1-4 alkyl or halogen; A 1 is a pyridazinyl, pyrimidinyl, pyrazinyl, pyridinyl or phenyl group, each of which is substituted by n occurrences of R 5 substituted; L is a linker; and A 2 is one of the following: R 1A is C 1-4 alkyl or C 3-4 cycloalkyl; R 2A independently represents C at each occurrence 1-4 alkyl or C 3-4 cycloalkyl; R 3A is a phenyl group substituted with 1, 2 or 3 substituents independently selected from a halogen group, a C1-C4 alkyl group or a C1-C4 haloalkyl group; R 4A is -(C 1-6 alkylene)-C(O)N(R 5A )(R 6A ), -(C 1-6 alkylene)-N(R 5A )C(O)R 7A , -(C 1-6 alkylene)-CO2R 7A , -(C 1-6 alkylene)-OC(O)R 7A , -(C 0-6 alkylene)-(5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur), -(C 1-6 alkylene)-cyano, C 1-6 alkyl or hydrogen; or R 4A and R 10A together with the carbon atom to which they are attached form a C 3-5 saturated carbocycle; R 5A and R 6A independently is hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl; or R 5A and R 6A together with the nitrogen atom to which they are attached form a 3- to 7-membered ring containing 1 nitrogen atom; R 7A is C 1-6 alkyl, -(C 1-6 alkylene)-(C 3-6 cycloalkyl) or C 3-6 cycloalkyl; R 8A independently represents C at each occurrence 1-4 alkyl or -N(R 9A )2; R 9A independently represents hydrogen or C at each occurrence 1-4 alkyl group; R 10A is hydrogen or C 1-4 alkyl; and m, n, p, and q are independently 0, 1, or 2.

2. The compound according to claim 1, wherein m is 0.

3. The compound according to claim 1, wherein R 1 is 4. The compound according to any one of claims 1 - 3, wherein R 2 is hydrogen.

5. The compound according to any one of claims 1 - 4, wherein R 3 is hydrogen.

6. The compound according to any one of claims 1 - 5, wherein the compound is a compound of formula I.

7. The compound according to any one of claims 1 - 5, wherein the compound is a compound of formula Ia or formula Ib or a pharmaceutically acceptable salt thereof:

8. The compound according to any one of claims 1 - 5, wherein the compound is a compound of formula Ic or a pharmaceutically acceptable salt thereof:

9. A compound according to any one of claims 1-5, wherein the compound is a compound of formula Id or a pharmaceutically acceptable salt thereof:

10. A compound according to any one of claims 1-9, wherein A 1 is a pyridazinyl group substituted with n occurrences of R 5 .

11. A compound according to any one of claims 1-9, wherein A 1 is 12. A compound according to any one of claims 1-9, wherein A 1 is a pyrimidinyl group substituted with n occurrences of R 5 .

13. A compound according to any one of claims 1-9, wherein A 1 is where * is the point of attachment to L.

14. A compound according to any one of claims 1-9, wherein A 1 is where * is the point of attachment to L.

15. A compound according to any one of claims 1-9, wherein A 1 is a pyrazinyl group substituted with n occurrences of R 5 .

16. A compound according to any one of claims 1-9, wherein A 1 is 17. A compound according to any one of claims 1-9, wherein A 1 is a pyridinyl group substituted with n occurrences of R 5 .

18. A compound according to any one of claims 1-9, wherein A 1 is where * is the point of attachment to L.

19. A compound according to any one of claims 1-9, wherein A 1 is a phenyl group substituted with n occurrences of R 5 .

20. A compound according to any one of claims 1-9, wherein A 1 is 21. A compound according to any one of claims 1-10, 12, 15, 17 or 19, wherein n is 0.

22. A compound according to any one of claims 1-21, wherein A 2Yes 23. The compound according to any one of claims 1-22, wherein R 3A is a phenyl group substituted by a halogen group.

24. The compound according to any one of claims 1-21, wherein A 2 is 25. The compound according to any one of claims 1-21 or 24, wherein R 4A is -(C 1-6 alkylene)-C(O)N(R 5A )(R 6A ).

26. The compound according to any one of claims 1-21 or 24, wherein R 4A is -(C 1-6 alkylene)-CO2R 7A .

27. The compound according to any one of claims 1-26, wherein R 1A is C 1-4 alkyl.

28. The compound according to any one of claims 1-26, wherein R 1A is methyl.

29. The compound according to any one of claims 1-28, wherein R 2A is C 1-4 alkyl.

30. The compound according to any one of claims 1-28, wherein R 2A is methyl.

31. The compound according to any one of claims 1-30, wherein p is 2.

32. The compound according to any one of claims 1-21, wherein A 2 is 33. The compound according to any one of claims 1-21, wherein A 2 is 34. The compound according to any one of claims 1-21, wherein A 2 is 35. The compound according to any one of claims 1-21, wherein A 2 is 36. The compound according to any one of claims 1-21, wherein A2 is 37. The compound according to any one of claims 1-21, wherein A 2 is 38. The compound according to any one of claims 1-21, wherein A 2 is 39. The compound according to any one of claims 1-21, wherein A 2 is 40. The compound according to any one of claims 1-21, wherein A 2 is 41. The compound according to any one of claims 1-21, wherein A 2 is 42. The compound according to any one of claims 1-21, wherein A 2 is 43. The compound according to any one of claims 1-21, wherein A 2 is 44. The compound according to any one of claims 1-21, wherein A 2 is 45. The compound according to any one of claims 1-21, wherein A 2 is 46. The compound according to any one of claims 1-21, wherein A 2 is 47. The compound according to any one of claims 1-21, wherein A 2 is 48. A compound represented by formula I*: or a pharmaceutically acceptable salt thereof; wherein: R 1 is a phenyl group substituted by a cyano group, a halogen, and m occurrences of R 4 substituted phenyl; R 2 and R 3 are independently hydrogen or C 1-4 alkyl; R 4 is C 1-4 alkyl; R 5 independently represents C at each occurrence 1-4 alkyl or halogen; A 1 is a pyridazinyl, pyrimidinyl, pyrazinyl, pyridinyl or phenyl group, each of which is substituted with n occurrences of R 5 substituted; L is a linker; and A 2 is one of the following: R 1A is C 1-4 alkyl or C 3-4 cycloalkyl; R 2A independently represents C at each occurrence 1-4 alkyl or C 3-4 cycloalkyl; R 4A is -(C 1-6 alkylene)-O-(C 1-6 alkyl), C 1-6 hydroxyalkyl, C 1-6 haloalkyl, -(C 1-6 alkylene)-C(O)N(R 5A )(R 6A ), -(C 1-6 alkylene)-N(R 5A )C(O)R 7A ), -(C 1-6 alkylene)-CO2R 7A ), -(C 1-6 alkylene)-OC(O)R 7A ), -(C 0-6 alkylene)-(5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur), -(C 1-6 alkylene)-cyano, C 1-6 alkyl or hydrogen; or R 4A and R 10A together with the carbon atom to which they are attached form a C 3-5 saturated carbocycle; R 5A and R 6A independently are hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl; or R 5A and R 6A together with the nitrogen atom to which they are attached form a 3- to 7-membered ring containing one nitrogen atom; R 7A is C 1-6 alkyl, -(C 1-6 alkylene)-(C 3-6 cycloalkyl) or C 3-6 cycloalkyl; R 8A independently represents C at each occurrence 1-4 alkyl or -N(R 9A )2; R 9A independently represents hydrogen or C at each occurrence 1-4 alkyl group; R 10A is hydrogen or C 1-4 alkyl; R 11A independently represents halogen each time it appears; and m, n, p, and q are independently 0, 1, or 2.

49. The compound according to claim 48, wherein the compound is a compound of formula Ic* or a pharmaceutically acceptable salt thereof:

50. The compound according to claim 48, wherein the compound is a compound of formula Id* or a pharmaceutically acceptable salt thereof:

51. The compound according to any one of claims 48 - 50, wherein A 1 is 52. The compound according to any one of claims 48 - 50, wherein A 1 is where * is the point of attachment to L.

53. The compound according to any one of claims 48 - 52, wherein A 2 is where q is 1.

54. The compound according to any one of claims 48 - 53, wherein R 4A is -(C 0-6 alkylene)-(5 - 6 - membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur).

55. The compound according to any one of claims 48 - 53, wherein R 4A is -(C 1-6 alkylene)-O-(C 1-6 alkyl), C 1-6 hydroxyalkyl or C 1-6 haloalkyl.

56. The compound according to any one of claims 48 - 52, wherein A 2 is 57. The compound according to any one of claims 48 - 52, wherein A 2 is one of the following:

58. The compound according to any one of claims 48 - 52, wherein A 2 is one of the following:

59. The compound according to any one of claims 48 - 52, wherein A 2 is 60. The compound according to any one of claims 48 - 52, wherein A 2 is 61. The compound according to any one of claims 1 - 60, wherein L is a divalent, saturated or unsaturated, straight - chain or branched - chain C 1-60 hydrocarbon chain, wherein 0 - 20 methylene units of said hydrocarbon are independently replaced by: -O-, -S-, -N(H)-, -N(C 1-6 alkyl)-, -OC(O)-, -C(O)O-, -S(O)-, -S(O)2-, -N(H)S(O)2-, -N(C 1-6 alkyl)S(O)2-, -S(O)2N(H)-, -S(O)2N(C 1-6 alkyl)-, -N(H)C(O)-, -N(C 1-6 alkyl)C(O)-, -C(O)N(H)-, -C(O)N(C 1-6 alkyl)-, -OC(O)N(H)-, -OC(O)N(C 1-6 alkyl)-, -N(H)C(O)O-, -N(C 1-6(alkyl)C(O)O-, -N(optionally substituted 3- to 10-membered carbocyclic group)-, optionally substituted 3- to 10-membered carbocyclic group, or optionally substituted 3- to 10-membered heterocyclic group containing 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

62. The compound according to any one of claims 1-60, wherein L is a divalent, saturated, straight-chain or branched-chain C 3-30 hydrocarbon chain, wherein 0-15 methylene units of the hydrocarbon are independently replaced by: -O-, -N(H)-, -N(C 1-6 alkyl)-, -OC(O)-, -C(O)O-, -N(H)C(O)-, -N(C 1-6 alkyl)C(O)-, -C(O)N(H)-, -C(O)N(C 1-6 alkyl)-, 3- to 10-membered carbocyclic group, or 3- to 10-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

63. The compound according to any one of claims 1-60, wherein L is a divalent, saturated, straight-chain or branched-chain C 3-30 hydrocarbon chain, wherein 0-15 methylene units of the hydrocarbon are independently replaced by: -O-, -N(H)-, -N(C 1-6 alkyl)-, -OC(O)-, -C(O)O-, -N(H)C(O)-, -N(C 1-6 alkyl)C(O)-, -C(O)N(H)- or -C(O)N(C 1-6 alkyl)-.

64. The compound according to any one of claims 1-60, wherein L is a divalent, saturated or unsaturated, straight-chain or branched-chain C 5-40 hydrocarbon chain, wherein 1-20 methylene units of the hydrocarbon are independently replaced by: -O-, -N(H)-, -N(C 1-6 alkyl)-, -N(H)C(O)-, -N(C 1-6 alkyl)C(O)-, -C(O)N(H)-, -C(O)N(C 1-6 alkyl)-, optionally substituted 3- to 10-membered carbocyclic group, or optionally substituted 3- to 10-membered heterocyclic group containing 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

65. The compound according to any one of claims 1-60, wherein L is -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(OCH2CH2) 1-15 -O-***, wherein *** is the point of attachment to A 2 of.

66. The compound according to any one of claims 1 - 60, wherein L is -(a 3 - 7 - membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(OCH2CH2) 1-5 -O-***, wherein *** is the point of attachment to A 2 67. The compound according to any one of claims 1 - 60, wherein L is -(a 3 - 7 - membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(OCH2CH2) 6-10 -O-***, wherein *** is the point of attachment to A 2 68. The compound according to any one of claims 1 - 60, wherein L is -piperidinyl-(OCH2CH2) 1-15 -O-***, wherein *** is the point of attachment to A 2 69. The compound according to any one of claims 1 - 60, wherein L is wherein *** is the point of attachment to A 2 70. The compound according to any one of claims 1 - 60, wherein L is wherein *** is the point of attachment to A 2 71. The compound according to any one of claims 1 - 60, wherein L is wherein *** is the point of attachment to A 2 72. The compound according to any one of claims 1 - 60, wherein L is -(a 3 - 7 - membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(OCH2CH2) 1-15 -N(H)C(O)-C 1-10 alkylene-***, -(a 3 - 7 - membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(OCH2CH2) 1-15 -N(C 1-4 alkyl)C(O)-C 1-10 alkylene-***, -(a 3 - 7 - membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(OCH2CH2) 1-15 -C(O)N(H)-C 1-10 alkylene-*** or -(a 3 - 7 - membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(OCH2CH2) 1-15 -C(O)N(C 1-4 alkyl)-C 1-10 alkylene-***, wherein *** is the point of attachment to A 2 ​​​​​​​ 73. A compound according to any one of claims 1 - 60, wherein L is - piperidinyl-(OCH2CH2) 1-5 -N(H)C(O)-C 1-5 alkylene-***, -piperidinyl-(OCH2CH2) 1-5 -N(C 1-4 alkyl)C(O)-C 1-5 alkylene-***, -piperidinyl-(OCH2CH2) 1-5 -C(O)N(H)-C 1-5 alkylene-*** or -piperidinyl-(OCH2CH2) 1-5 -C(O)N(C 1-4 alkyl)-C 1-5 alkylene-***, wherein *** is the point of attachment to A 2 .

74. A compound according to any one of claims 1 - 60, wherein L is -(3 - 7 - membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(OCH2CH2) 1-10 -***, -(3 - 7 - membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-10 alkylene)-O-*** or -(3 - 7 - membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-C 1-10 alkylene, wherein *** is the point of attachment to A 2 .

75. A compound according to any one of claims 1 - 60, wherein L is -piperidinyl-(OCH2CH2) 1-5 -***, -piperidinyl-(C 0-5 alkylene)-O-*** or -piperidinyl-(C 1-5 alkylene)-***, wherein *** is the point of attachment to A 2 .

76. A compound according to any one of claims 1 - 60, wherein L is -(3 - 7 - membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-X 1 -***, wherein *** is the point of attachment to A 2 and X 1 is (i)C 1-10 alkylene, wherein 1 or 2 methylenes are optionally replaced by -O-, -N(H)- or -N(C 1-4 alkyl)-, (ii) a 3 - 7 - membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen, or (iii)-(3 - 7 - membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(C 1-10 alkylene)-.

77. The compound according to any one of claims 1-60, wherein L is -(piperidinyl)-X 1 -***, wherein *** is the point of attachment to A 2 and X 1 is (i) C 1-5 alkylene, wherein one or two methylene groups are optionally replaced by -O-, -N(H)- or -N(C 1-4 alkyl)-, (ii) a 3-4 membered monocyclic saturated heterocycle containing one heteroatom selected from nitrogen, or (iii) -(a 3-4 membered monocyclic saturated heterocycle containing one heteroatom selected from nitrogen)-(C 1-5 alkylene)-.

78. The compound according to any one of claims 1-60, wherein L is wherein *** is the point of attachment to A 2 and X 1 is (i) C 1-10 alkylene, wherein one or two methylene groups are optionally replaced by -O-, -N(H)- or -N(C 1-4 alkyl)-, (ii) a 3-7 membered monocyclic saturated heterocycle containing one or two heteroatoms selected from nitrogen, or (iii) -(a 3-7 membered monocyclic saturated heterocycle containing one or two heteroatoms selected from nitrogen)-(C 1-10 alkylene)-.

79. The compound according to any one of claims 1-60, wherein L is -(piperazinyl)-X 1 -***, wherein *** is the point of attachment to A 2 and X 1 is (i) C 1-5 alkylene, wherein one or two methylene groups are optionally replaced by -O-, (ii) a 3-4 membered monocyclic saturated heterocycle containing one heteroatom selected from nitrogen, or (iii) -(a 3-4 membered monocyclic saturated heterocycle containing one heteroatom selected from nitrogen)-(C 1-5 alkylene)-.

80. The compound according to any one of claims 1-60, wherein L is wherein *** is the point of attachment to A 2 and X 1 is (i) C 1-10 alkylene, wherein one or two methylene groups are optionally replaced by -O-, (ii) a 3-7 membered monocyclic saturated heterocycle containing one or two heteroatoms selected from nitrogen, or (iii) -(a 3-7 membered monocyclic saturated heterocycle containing one or two heteroatoms selected from nitrogen)-(C 1-10 alkylene)-.

81. A compound according to any one of claims 1 - 60, wherein L is -(a 3 - 7 - membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-X 2 -(C 1-10 alkylene)-***, wherein *** is the point of attachment to A 2 and X 2 is -O-, -N(H)- or -N(C 1-6 alkyl)-.

82. A compound according to any one of claims 1 - 60, wherein L is -(piperidinyl)-X 2 -(C 1-10 alkylene)-***, wherein *** is the point of attachment to A 2 and X 2 is -O-, -N(H)- or -N(C 1-6 alkyl)-.

83. A compound according to any one of claims 1 - 60, wherein L is -(piperidinyl)-X 2 -(a 3 - 7 - membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-***, wherein *** is the point of attachment to A 2 and X 2 is -O-, -N(H)- or -N(C 1-6 alkyl)-.

84. A compound according to any one of claims 1 - 60, wherein L is wherein *** is the point of attachment to A 2 and X 2 is -O-, -N(H)- or -N(C 1-6 alkyl)-.

85. A compound according to any one of claims 1 - 60, wherein L is wherein *** is the point of attachment to A 2 and X 2 is -O-, -N(H)- or -N(C 1-6 alkyl)-.

86. A compound according to any one of claims 81 - 85, wherein X 2 is -O-.

87. A compound according to any one of claims 1 - 60, wherein L is -(a 3 - 7 - membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-X 1 -***, wherein *** is the point of attachment to A 2 and X 1 is -(OCH2CH2) 1-10 , wherein 1 CH2 group is optionally substituted with -C(H)(C3-6 cycloalkyl)-substitution.

88. A compound according to any one of claims 1-60, wherein L is a 7-11 membered spiro or fused bicyclic saturated heterocycle containing 1, 2 or 3 heteroatoms selected from nitrogen and oxygen.

89. A compound according to any one of claims 1-60, wherein L is a 7-8 membered spiro or fused bicyclic saturated heterocycle containing 2 heteroatoms selected from nitrogen.

90. A compound according to any one of claims 1-60, wherein L is -(a 3-7 membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-X 3 -(a 3-7 membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-, wherein X 3 is C 1-10 alkylene, -O-, -N(H)-, -N(C 1-4 alkyl)- or a bond.

91. A compound according to any one of claims 1-60, wherein L is -(piperidinyl)-(C 1-5 alkylene)-(piperazinyl)-***, wherein *** is the point of attachment to A 2 and.

92. A compound according to any one of claims 1-60, wherein L is -(piperazinyl)-(azetidinyl)-*** or (azetidinyl)-(piperazinyl)-***, wherein *** is the point of attachment to A 2 and.

93. A compound according to any one of claims 1-60, wherein L is -(a 3-7 membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-X 3 -(C 3-6 cycloalkylene)-O-***, -(a 3-7 membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-X 3 -(C 3-6 cycloalkylene)-N(H)-*** or -(a 3-7 membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-X 3 -(C 3-6 cycloalkylene)-N(C 1-4 alkyl)-***, wherein *** is the point of attachment to A 2 and X 3 is C 1-10 alkylene, -O-, -N(H)-, -N(C 1-4 alkyl)- or a bond.

94. A compound according to any one of claims 1-60, wherein L is -(piperidinyl)-X 3 -(C 3-6-(cycloalkylidene)-O-***, -(piperidinylidene)-X 3 -(C 3-6 -(cycloalkylidene)-N(H)-*** or -(piperidinylidene)-X 3 -(C 3-6 -(cycloalkylidene)-***, where *** is the point of attachment to A 2 and X 3 is C 1-10 -alkylene, -O-, -N(H)-, -N(C 1-4 -alkyl)- or a bond.

95. The compound according to any one of claims 1 - 60, wherein L has the formula -(C 0-12 -alkylene)-(optionally substituted 3 - 40 - membered heteroalkylene)-(C 0-12 -alkylene)-.

96. The compound according to any one of claims 1 - 60, wherein L is -(spiro 6 - 10 - membered heterocyclic group)-O-***, where *** is the point of attachment to A 2 and.

97. The compound according to any one of claims 1 - 60, wherein L is -(spiro 6 - 10 - membered heterocyclic group)-(C 0-12 -alkylene)-***, where *** is the point of attachment to A 2 and.

98. The compound according to any one of claims 1 - 60, wherein L is one of the following: where *** is the point of attachment to A 2 and.

99. The compound according to any one of claims 1 - 60, wherein L is one of the following: where *** is the point of attachment to A 2 and.

100. The compound according to any one of claims 1 - 60, wherein L is one of the following: where *** is the point of attachment to A 2 and.

101. The compound according to any one of claims 1 - 60, wherein L is where *** is the point of attachment to A 2 and.

102. The compound according to any one of claims 1 - 60, wherein L is where *** is the connection point with A 2 .

103. The compound according to any one of claims 1 - 60, wherein L is -(an 8 - 12 - membered spiroheterocyclic group containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-(C 3-4 subcycloalkyl)-***, -(an 8 - 12 - membered spiroheterocyclic group containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-(C 0-4 alkylene)-***, -(an 8 - 12 - membered spiroheterocyclic group containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-C(O)-(C 1-4 alkylene)-***, -(a 5 - 6 - membered saturated monocyclic subheterocyclic group containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-(a 3 - 5 - membered saturated monocyclic subheterocyclic group containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-***, -(a 5 - 6 - membered saturated monocyclic subheterocyclic group containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-O-***, -(a 5 - 6 - membered saturated monocyclic subheterocyclic group containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-(C 0-4 alkylene)-***, -(a 5 - 6 - membered saturated monocyclic subheterocyclic group containing 1 or 2 heteroatoms)-(C 0-4 alkylene)-O-***, -(an 8 - 12 - membered spiroheterocyclic group containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-C(O))-***, -(an 8 - 12 - membered spiroheterocyclic group containing 1 or 2 heteroatoms selected from nitrogen)-O-(C 0-6 alkylene)-***, -(an 8 - 12 - membered spiroheterocyclic group containing 1 or 2 heteroatoms selected from nitrogen)-(C 1-6 alkylene)-O-(C 0-6 alkylene)-***, -(a 5 - 6 - membered saturated monocyclic subheterocyclic group containing 1 or 2 heteroatoms)-C(O)N(H)-(C 0-6 alkylene)-***, -(N(C 1-6 alkyl)-(C 0-6 alkylene)-C(O)N(H)-(C 0-6 alkylene)-***, -(an 8 - 12 - membered spiroheterocyclic group containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-(C 2-4 alkynyl)-***, -(a 5 - 6 - membered saturated monocyclic subheterocyclic group containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-(C 1-6 alkyl)-(a 3 - 5 - membered saturated monocyclic subheterocyclic group containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-***, -(a 5 - 6 - membered saturated monocyclic subheterocyclic group containing 1 or 2 heteroatoms selected from nitrogen)-C(O)N(H)-(C0-6 -(alkylene)-N(H))-***, -(C(O)N(H)-(C 0-6 -(alkylene)-(5- or 6-membered saturated monocyclic heterocyclic group containing 1 or 2 heteroatoms)-***, -(5- or 6-membered saturated monocyclic heterocyclic group containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-N(C 1-6 -(alkyl)-(5- or 6-membered saturated monocyclic heterocyclic group containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-O-***, -C(O)-(5- or 6-membered saturated monocyclic heterocyclic group containing 1 heteroatom selected from nitrogen)-C(O)-***, -(C 0-6 -(alkylene)-(5- or 6-membered saturated monocyclic heterocyclic group containing 1 heteroatom selected from nitrogen)-C(O)-***, -(5- or 6-membered saturated monocyclic heterocyclic group containing 1 heteroatom selected from nitrogen)-C(O)-(C 0-6 -(alkylene)***, -C(O)-(5- or 6-membered saturated monocyclic heterocyclic group containing 1 heteroatom selected from nitrogen)-(C 1-6 -(alkylene)-***, -(C(O)N(H)-(C 1-6 -(alkylene)-C(O)N(H)-(C 0-6 -(alkylene)-*** or -(8- to 11-membered fused bicyclic heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-(C 1-4 -(alkylene)-***, wherein *** is the point of attachment to A 2 of 104. The compound according to any one of claims 1 - 60, wherein L is -N(C 1-6 -(alkyl)-(5- or 6-membered saturated monocyclic heterocyclic group containing 1 heteroatom selected from nitrogen)-C(O)-(C 0-6 -(alkylene)-***, -(5- or 6-membered saturated monocyclic heterocyclic group containing 1 heteroatom selected from nitrogen)-(5- or 6-membered saturated monocyclic heterocyclic group containing 1 heteroatom selected from nitrogen)-(C 0-4 -(alkylene)-O-***, -(C 0-6 -(alkylene)-N(H)C(O)N(H)-(C 0-6 -(alkylene)-***, -N(H)-(C 0-6 -(alkylene)-(5- or 6-membered saturated monocyclic heterocyclic group containing 1 heteroatom selected from nitrogen)-(C 0-6 -(alkylene)-***, -(C 0-6 -(alkylene)-C(O)-(5- or 6-membered saturated monocyclic heterocyclic group containing 1 heteroatom selected from nitrogen)-(C 0-6 -(alkylene)-***, -(C 0-6(Alkylene)-(5- or 6-membered saturated monocyclic heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen)-C(O)N(C 1-6 Alkyl)-(C 0-6 Alkylene)-***, -(C 0-6 Alkylene)-(5- or 6-membered saturated monocyclic heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-6 Alkylene)-N(C 1-6 Alkyl)-(3- to 6-membered saturated monocyclic heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen)-***, -(4- to 6-membered monocyclic heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-6 Alkylene)-O-(5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen)-O-***, -(4- to 6-membered monocyclic heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-6 Alkylene)-(5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen)-O-***, -(4- to 6-membered monocyclic heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-6 Alkylene)-(5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen)-***, -(8- to 12-membered spiro heterocyclic group substituted with 1 or 2 fluorines and containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-(C 1-4 Alkylene)-***, -(5- or 6-membered saturated monocyclic heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-4 Alkylene)-(C 3-6 Subcycloalkyl)-(C 0-4 Alkylene)-O-***, -(5- or 6-membered saturated monocyclic heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-4 Alkylene)-(C 3-6 Subcycloalkyl)-(C 0-4 Alkylene)-***, -(C 0-4 Alkylene)-(8- to 12-membered spiro heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-***, -(C 0-4 Alkylene)-(C 3-6 Subcycloalkyl)-(C 2-4 Subalkynyl)-***, -(C 0-4 Alkylene)-(8- to 10-membered fused bicyclic heterocyclic group substituted with 1 or 2 fluorines and containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-4 Alkylene)-***, -(8- to 12-membered spiro heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-O-***, -(8- to 12-membered spiro heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-(C 0-4-(alkylene)-(5- or 6-membered saturated monocyclic heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen)-***, -(C 0-4 -(alkylene)-(4- to 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen)-(phenyl group substituted with trifluoromethyl)-(C 0-4 -(alkylene)-N(H)-***, or -(5- or 6-membered saturated monocyclic heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen)-C(O)-(5- or 6-membered saturated monocyclic heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-6 -(alkylene)-***, -(C 3-6 -(cycloalkylene)-C(O)N(C 1-6 -alkyl)(C 0-6 -(alkylene)-***, -(5- or 6-membered saturated monocyclic heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen)-(phenyl group substituted with 0 or 1 occurrence of methyl or halogen)-(C 0-6 -(alkylene)-***, -(5- or 6-membered saturated monocyclic heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-6 -(alkylene)-(5- or 6-membered saturated monocyclic heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen and substituted with oxo group)-(C 0-6 -(alkylene)-***, -(8- to 12-membered spiro heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen and substituted with C 1-4 -alkyl)-(C 0-6 -(alkylene)-(O) 0-1 -***, -(C 2-4 -(alkynylene)-(8- to 12-membered spiro heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-(C 0-4 -(alkylene)-***, -(C 0-4 -(alkylene)-(C 3-7 -(cycloalkylene)-(C 2-4 -(alkynylene)-***, -(C 1-4 -(alkylene)-(8- to 12-membered spiro heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-(C 0-4 -(alkylene)-***, -(C 1-4 -(alkylene)-(5- to 7-membered saturated heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-(C 0-4 -(alkylene)-***, -(C 0-4 -(alkylene)-(5- to 7-membered saturated heterocyclic group containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-(C 2-4 -(alkenylene)-*** or -(C 0-4-(Alkylene)-(a 6-8-membered saturated heterocyclic group substituted by 1 or 2 fluorines and containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-(C 0-4 -alkylene)-***, wherein *** is the point of attachment to A 2 of the formula.

105. A compound represented by formula Ie, formula If or formula Ig, or a pharmaceutically acceptable salt thereof: wherein L is one of the following: (i) a 7-11-membered spiro or fused bicyclic saturated heterocycle containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen; (ii)-(a 7-11-membered spiro saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(C 2-4 -alkynylene)-***, wherein *** is the point of attachment to the phenylene group in the formula; or (iii)-N(C 1-4 -alkyl)-(C 1-6 -alkylene)-(a 4-7-membered saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen and oxygen)-***, wherein *** is the point of attachment to the phenylene group in the formula.

106. The compound according to claim 105, wherein the compound is represented by formula Ih or a pharmaceutically acceptable salt thereof:

107. The compound according to claim 105, wherein the compound is represented by formula Ii or a pharmaceutically acceptable salt thereof:

108. The compound according to claim 105, wherein the compound is represented by formula Ij or a pharmaceutically acceptable salt thereof:

109. The compound according to claim 105, wherein the compound is represented by formula Ik or a pharmaceutically acceptable salt thereof:

110. The compound according to claim 105, wherein the compound is represented by formula Il or a pharmaceutically acceptable salt thereof:

111. The compound according to any one of claims 105-110, wherein L is a 7-11-membered spiro or fused bicyclic saturated heterocycle containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen.

112. The compound according to any one of claims 105 - 110, wherein L is -(7 - 11 - membered spiro saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(C 2-4 alkynylene)-***, where *** is the point of attachment to the phenylene group in the formula.

113. The compound according to any one of claims 105 - 110, wherein L is -N(C 1-4 alkyl)-(C 1-6 alkylene)-(4 - 7 - membered saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen and oxygen)-***, where *** is the point of attachment to the phenylene group in the formula.

114. The compound according to any one of claims 105 - 110, wherein L is one of the following: where *** is the point of attachment to the phenylene group in the formula.

115. A compound in Table 1 or a pharmaceutically acceptable salt thereof.

116. The compound according to claim 115, wherein the compound is any one of Compounds I - 1 to I - 199 in Table 1 or a pharmaceutically acceptable salt thereof.

117. A compound represented by Formula II: or a pharmaceutically acceptable salt thereof; wherein: TPL is a group defined by formula II-1, which is substituted by one occurrence of R II-1A where formula II-1 is represented by the following: or a pharmaceutically acceptable salt thereof; wherein: R II-1A is the key for L; R 1 is a phenyl group substituted by a cyano group, a halogen, and R which appears m times 4 substituted phenyl; R 2 and R 3 are independently hydrogen or a C 1-4 alkyl group; R 4 is C 1-4 alkyl; R 5 independently represents C at each occurrence 1-4 alkyl or halogen; A 1 is a pyridazinyl, pyrimidinyl, pyrazinyl, pyridyl or phenyl group, each of which is substituted by n occurrences of R 5 substituted; L is a linker; EPL is a moiety that binds to BRD4; and m and n are independently 0, 1, or 2.

118. The compound according to claim 117, wherein the TPL is R II-1A substituted 119. The compound according to claim 117, wherein the TPL is 120. A compound according to any one of claims 117 - 119, wherein said EPL is defined by formula II - 2, which is substituted by one occurrence of R II-2A wherein formula II - 2 is represented as follows: wherein R II-2A is a bond to L; R 1A is C 1-4 alkyl or C 3-4 cycloalkyl; R 2A independently represents C 1-4 alkyl or C 3-4 cycloalkyl at each occurrence; R 3A is phenyl substituted by 1, 2 or 3 substituents independently selected from halo, C1 - C4 alkyl or C1 - C4 haloalkyl; R 4A is -(C 1-6 alkylene)-C(O)N(R 5A )(R 6A ), -(C 1-6 alkylene)-N(R 5A )C(O)R 7A ), -(C 1-6 alkylene)-CO2R 7A ), -(C 1-6 alkylene)-OC(O)R 7A ), -(C 0-6 alkylene)-(a 5 - 6 - membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur), -(C 1-6 alkylene)-cyano, C 1-6 alkyl or hydrogen; or R 4A and R 10A together with the carbon atom to which they are attached form a C 3-5 saturated carbocyclic ring; R 5A and R 6A are independently hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl; or R 5A and R 6A together with the nitrogen atom to which they are attached form a 3 - 7 - membered ring containing 1 nitrogen atom; R 7A is C 1-6 alkyl, -(C 1-6 alkylene)-(C 3-6 cycloalkyl) or C 3-6 cycloalkyl; R 8A independently represents C at each occurrence 1-4 alkyl or -N(R 9A )2; R 9A independently represents hydrogen or C at each occurrence 1-4 alkyl; R 10A is hydrogen or C 1-4 alkyl; and p and q are independently 0, 1 or 2.

121. The compound according to any one of claims 117 - 119, wherein the EPL is wherein each R at one occurrence II -2A is substituted, where R II-2A is a bond to L.

122. The compound according to any one of claims 117 - 119, wherein the EPL is 123. The compound according to any one of claims 117 - 119, wherein the EPL is 124. The compound according to any one of claims 117 - 123, wherein L is a divalent, saturated or unsaturated, straight-chain or branched-chain C 1-60 hydrocarbon chain, wherein 0 - 20 methylene units of the hydrocarbon are independently replaced by: -O-, -S-, -N(H)-, -N(C 1-6 alkyl)-, -OC(O)-, -C(O)O-, -S(O)-, -S(O)2-, -N(H)S(O)2-, -N(C 1-6 alkyl)S(O)2-, -S(O)2N(H)-, -S(O)2N(C 1-6 alkyl)-, -N(H)C(O)-, -N(C 1-6 alkyl)C(O)-, -C(O)N(H)-, -C(O)N(C 1-6 alkyl)-, -OC(O)N(H)-, -OC(O)N(C 1-6 alkyl)-, -N(H)C(O)O-, -N(C 1-6 alkyl)C(O)O-, an optionally substituted 3 - 10 membered carbocyclic group, or an optionally substituted 3 - 10 membered heterocyclic group containing 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

125. The compound according to any one of claims 117 - 123, wherein L is a divalent, saturated, straight-chain or branched-chain C 3-30A hydrocarbon chain, wherein 0-15 methylene units of the hydrocarbon are independently replaced by: -O-, -N(H)-, -N(C 1-6 alkyl)-, -OC(O)-, -C(O)O-, -N(H)C(O)-, -N(C 1-6 alkyl)C(O)-, -C(O)N(H)-, -C(O)N(C 1-6 alkyl)-, a 3-10 membered carbocyclic group, or a 3-10 membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

126. The compound according to any one of claims 117-123, wherein L is a divalent, saturated, straight or branched chain C 3-30 hydrocarbon chain, wherein 0-15 methylene units of the hydrocarbon are independently replaced by: -O-, -N(H)-, -N(C 1-6 alkyl)-, -OC(O)-, -C(O)O-, -N(H)C(O)-, -N(C 1-6 alkyl)C(O)-, -C(O)N(H)- or -C(O)N(C 1-6 alkyl)-.

127. The compound according to any one of claims 117-123, wherein L is where *** is the point of attachment to A 2 .

128. The compound according to any one of claims 117-123, wherein L is where *** is the point of attachment to A 2 .

129. The compound according to any one of claims 117-123, wherein L is -(an 8-12 membered spiro heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-(C 3-4 subcycloalkyl)-***, -(an 8-12 membered spiro heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-(C 0-4 alkylene)-***, -(an 8-12 membered spiro heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-C(O)-(C 1-4 alkylene)-***, -(a 5-6 membered saturated monocyclic subheterocyclic group containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-(a 3-5 membered saturated monocyclic subheterocyclic group containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-***, -(a 5-6 membered saturated monocyclic subheterocyclic group containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-O-***, -(a 5-6 membered saturated monocyclic subheterocyclic group containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-(C 0-4-alkylene)-***, -(5- or 6-membered saturated monocyclic heteroalkyl group containing 1 or 2 heteroatoms)-(C 0-4 -alkylene)-O-***, -(8- to 12-membered spiroheterocyclic group containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-C(O))-***, -(8- to 12-membered spiroheterocyclic group containing 1 or 2 heteroatoms selected from nitrogen)-O-(C 0-6 -alkylene)-***, -(8- to 12-membered spiroheterocyclic group containing 1 or 2 heteroatoms selected from nitrogen)-(C 1-6 -alkylene)-O-(C 0-6 -alkylene)-***, -(5- or 6-membered saturated monocyclic heteroalkyl group containing 1 or 2 heteroatoms)-C(O)N(H)-(C 0-6 -alkylene)-***, -(N(C 1-6 -alkyl)-(C 0-6 -alkylene)-C(O)N(H)-(C 0-6 -alkylene)-***, -(8- to 12-membered spiroheterocyclic group containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-(C 2-4 -alkynylene)-***, -(5- or 6-membered saturated monocyclic heteroalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-(C 1-6 -alkyl)-(5- or 6-membered saturated monocyclic heteroalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-***, -(5- or 6-membered saturated monocyclic heteroalkyl group containing 1 or 2 heteroatoms selected from nitrogen)-C(O)N(H)-(C 0-6 -alkylene)-N(H))-***, -(C(O)N(H)-(C 0-6 -alkylene)-(5- or 6-membered saturated monocyclic heteroalkyl group containing 1 or 2 heteroatoms)-***, -(5- or 6-membered saturated monocyclic heteroalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-N(C 1-6 -alkyl)-(5- or 6-membered saturated monocyclic heteroalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-O-***, -C(O)-(5- or 6-membered saturated monocyclic heteroalkyl group containing 1 or 2 heteroatoms selected from nitrogen)-C(O)-***, -(C 0-6 -alkylene)-(5- or 6-membered saturated monocyclic heteroalkyl group containing 1 or 2 heteroatoms selected from nitrogen)-C(O)-***, -(5- or 6-membered saturated monocyclic heteroalkyl group containing 1 or 2 heteroatoms selected from nitrogen)-C(O)-(C 0-6 -alkylene)***, -C(O)-(5- or 6-membered saturated monocyclic heteroalkyl group containing 1 or 2 heteroatoms selected from nitrogen)-(C 1-6 -alkylene)-***, -(C(O)N(H)-(C 1-6alkylene)-C(O)N(H)-(C 0-6 alkylene)-*** or -(8-11-membered fused bicyclic heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-(C 1-4 alkylene)-***, wherein *** is the point of attachment to A 2 of.

130. The compound according to any one of claims 117-123, wherein L is -N(C 1-6 alkyl)-(5-6-membered saturated monocyclic heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen)-C(O)-(C 0-6 alkylene)-***, -(5-6-membered saturated monocyclic heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen)-(5-6-membered saturated monocyclic heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-4 alkylene)-O-***, -(C 0-6 alkylene)-N(H)C(O)N(H)-(C 0-6 alkylene)-***, -N(H)-(C 0-6 alkylene)-(5-6-membered saturated monocyclic heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-6 alkylene)-***, -(C 0-6 alkylene)-C(O)-(5-6-membered saturated monocyclic heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-6 alkylene)-***, -(C 0-6 alkylene)-(5-6-membered saturated monocyclic heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen)-C(O)N(C 1-6 alkyl)-(C 0-6 alkylene)-***, -(C 0-6 alkylene)-(5-6-membered saturated monocyclic heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-6 alkylene)-N(C 1-6 alkyl)-(3-6-membered saturated monocyclic heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen)-***, -(4-6-membered monocyclic heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-6 alkylene)-O-(5-6-membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen)-O-***, -(4-6-membered monocyclic heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-6 alkylene)-(5-6-membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen)-O-***, -(4-6-membered monocyclic heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-6-(alkylene)-(5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen)-***, -(8- to 12-membered spiroheterocyclic group substituted with 1 or 2 fluorines and containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-(C 1-4 -(alkylene)-***, -(5- or 6-membered saturated monocyclic heteroalkyl group containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-4 -(alkylene)-(C 3-6 -(subcycloalkyl)-(C 0-4 -(alkylene)-O-***, -(5- or 6-membered saturated monocyclic heteroalkyl group containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-4 -(alkylene)-(C 3-6 -(subcycloalkyl)-(C 0-4 -(alkylene)-***, -(C 0-4 -(alkylene)-(8- to 12-membered spiroheterocyclic group containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-***, -(C 0-4 -(alkylene)-(C 3-6 -(subcycloalkyl)-(C 2-4 -(alkynyl)-***, -(C 0-4 -(alkylene)-(8- to 10-membered fused bicyclic heterocyclic group substituted with 1 or 2 fluorines and containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-4 -(alkylene)-***, -(8- to 12-membered spiroheterocyclic group containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-O-***, -(8- to 12-membered spiroheterocyclic group containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-(C 0-4 -(alkylene)-(5- or 6-membered saturated monocyclic heteroalkyl group containing 1 or 2 heteroatoms selected from nitrogen)-***, -(C 0-4 -(alkylene)-(4- to 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen)-(phenyl group substituted with trifluoromethyl)-(C 0-4 -(alkylene)-N(H)-***, or -(5- or 6-membered saturated monocyclic heteroalkyl group containing 1 or 2 heteroatoms selected from nitrogen)-C(O)-(5- or 6-membered saturated monocyclic heteroalkyl group containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-6 -(alkylene)-***, -(C 3-6 -(subcycloalkyl)-C(O)N(C 1-6 alkyl)(C 0-6 -(alkylene)-***, -(5- or 6-membered saturated monocyclic heteroalkyl group containing 1 or 2 heteroatoms selected from nitrogen)-(phenyl group substituted with 0 or 1 occurrence of methyl or halogen)-(C 0-6 -(alkylene)-***, -(5- or 6-membered saturated monocyclic heteroalkyl group containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-6(Alkylene)-(a 5- or 6-membered saturated monocyclic heteroaryl group containing 1 or 2 heteroatoms selected from nitrogen and substituted by an oxo group)-(C 0-6 (Alkylene)-***, -(an 8- to 12-membered spiroheterocyclic group containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen and substituted by C 1-4 alkyl)-(C 0-6 (Alkylene)-(O) 0-1 ***, -(C 2-4 (Alkynylene)-(an 8- to 12-membered spiroheterocyclic group containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-(C 0-4 (Alkylene)-***, -(C 0-4 (Alkylene)-(C 3-7 (Cycloalkylene)-(C 2-4 (Alkynylene)-***, -(C 1-4 (Alkylene)-(an 8- to 12-membered spiroheterocyclic group containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-(C 0-4 (Alkylene)-***, -(C 1-4 (Alkylene)-(a 5- to 7-membered saturated heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-(C 0-4 (Alkylene)-***, -(C 0-4 (Alkylene)-(a 5- to 7-membered saturated heterocyclic group containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-(C 2-4 (Alkenylene)-*** or -(C 0-4 (Alkylene)-(a 6- to 8-membered saturated heterocyclic group substituted by 1 or 2 fluorines and containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-(C 0-4 (Alkylene)-***, where *** is the point of attachment to A 2 of.

131. A pharmaceutical composition comprising the compound according to any one of claims 1-131 and a pharmaceutically acceptable carrier.

132. A method for treating cancer, the method comprising administering to a patient in need thereof a therapeutically effective amount of the compound according to any one of claims 1-131 to treat the cancer.

133. The method according to claim 132, wherein the cancer is ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, prostate cancer, testicular cancer, breast cancer, brain cancer, lung cancer, oral cancer, esophageal cancer, head and neck cancer, gastric cancer, colon cancer, rectal cancer, skin cancer, sebaceous gland cancer, bile duct cancer, gallbladder cancer, liver cancer, pancreatic cancer, bladder cancer, urinary tract cancer, kidney cancer, eye cancer, thyroid cancer, lymphoma or leukemia.

134. The method according to claim 132, wherein the cancer is prostate cancer.

135. A method for causing cancer cell death, the method comprising contacting a cancer cell with an effective amount of the compound according to any one of claims 1-131 to cause the death of the cancer cell.

136. The method according to claim 135, wherein the cancer cell is selected from ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, prostate cancer, testicular cancer, breast cancer, brain cancer, lung cancer, oral cancer, esophageal cancer, head and neck cancer, gastric cancer, colon cancer, rectal cancer, skin cancer, sebaceous gland cancer, bile duct cancer, gallbladder cancer, liver cancer, pancreatic cancer, bladder cancer, urinary tract cancer, kidney cancer, eye cancer, thyroid cancer, lymphoma or leukemia cells.

137. The method according to claim 135, wherein the cancer cell is a prostate cancer cell.

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